In the first book in the series, The Maze of Bones, Amy and Dan's grandmother Grace dies and leaves them with a choice. They can inherit $1 million or have the opportunity to search for 39 clues that, once found, will make them the most powerful people in the world. Amy (14), her brother, Dan (11), and a number of their corrupt relatives have chosen to hunt for the clues.
The year is 1507, and Gideon Cahill is working in Damien Vesper's laboratory, searching for the cure for Black Death, which is killing the peasants in the region. Instead of creating a cure, he comes up with a serum that makes a person healthier, stronger, wiser and bolder than he was before. He samples the serum and finds his strengthened abilities also destroy his body. He plans to remedy this before it kills him. Damien gets word from a housekeeper that Gideon is onto something and calls him in for a meeting.
When Gideon refuses to release information about his findings, Damien attempts to kill him and witnesses firsthand the extreme strength and agility that Gideon now has. Damien wants the serum to increase his power and wealth, not to save the dying. Gideon ends his friendship with Damien and returns home to his family. He gives a gift to each of his children: a green vial containing a portion of the serum's ingredients and the recipe for what is in the vials. Combining their ingredients will create the master serum. The portion in each of their vials will only increase their strength according to their natural talents.
Gideon knows that Damien will be coming for him and prepares his family to flee in the night. Luke, the eldest, drinks his vial and challenges Gideon for the master serum. Gideon begs his son to work with his siblings to perfect the serum and use it for good. As the children are leaving the island, Damien comes to the lab to kill Gideon and steal the serum. Gideon triggers an explosive and blows up the lab, giving his life to keep the serum out of Damien's hands. The family sees the explosion and runs back for their father. The boys begin casting blame on each other, and the fighting escalates until Luke runs off and Jane follows. In their anger, Thomas and Katherine join together and tell their mother they are finished with the family.
Gideon's wife, Olivia, is left alone, a widow with a great secret. She is pregnant with Madeleine and will raise her to bring their family together again. Damien promises to remember her and spends his life searching for the serum. Olivia takes the ring that Gideon received from his father and leaves the island to start over on her own.
The year is 1526. Madeleine Cahill is raised as "Maddy Babbit" and trains in alchemy with her mother. She is never to speak the name "Cahill," and she lives her life surrounded by lies. A schoolteacher reveals Madeleine's true identity, and Damien Vesper arrives to destroy Olivia's home. Madeleine runs for her life and remembers the promises she made to her mother: keep the ring safe, never let anyone abuse the power of the 39 clues and unite the Cahills when the time is right.
She begins searching for her siblings. Luke is found working in the palace of King Henry, and Madeleine is hired to be his son's governess. When Luke discovers her ring, he has Madeleine thrown into jail for theft. He remembers the ring from his father's hand and wants to know how she came upon it. When she reveals her identity, Luke doesn't believe her and plans to have her burned at the stake. Madeleine escapes from prison and, after a jousting match with the king, chases down Damien Vesper's carriage. The ring has been stolen from Luke by his servant and given to Damien. The ring has now made it into the hands of Vesper. Madeleine, disguised as a thief, attacks the carriage. After it crashes, Madeleine retrieves the ring and leaves a message in the sand for Luke: "Beware the Madrigals."
In 1942, Grace Cahill is 13 years old and is responsible for herself and her siblings. Her mother died giving birth to a child named Fiske. Her father is heartbroken at the loss of his wife, and abandons his children. Late one night, a message in Morse code is sent to the house, and Grace is able to decipher it. She takes it upon herself to hire a pilot to fly her into war torn Casablanca, with the hopes of meeting Gen. Patton and passing on the message. The pilot is killed on descent, and Grace is left to crash-land the plane and make her way on her own. She has a broken arm. She blocks the road, so some soldiers stop to help her.
With the mention of the name "Cahill," the American troops are happy to connect her with Patton. He assures her that he will look for the clue that came in the message and locate her father. Grace doesn't believe that Patton will be able to take care of matters because of all his commitments in the war, so she sets out to find the clue on her own. The translated message leads her to a bar in Ancienne Medina that has a statue of a bull in the courtyard. She is to look for the bull's eye, but it is missing.
Patton moves out of the shadows and tells her that the Vespers have beaten them to the prize. Grace notices a ring shaped bulge in Patton's pocket and discovers that he is not a Cahill but a Vesper. That night, while Patton sleeps, Grace crawls through his open window and takes the ring from his wooden valet. She digs a hole in her cast to hide the ring and then returns home to her family. The ring is once again with the Cahills.
At the end of the clue hunt, Dan and Amy can't wait to return to their normal lives. However, Dan finds normal life to be boring. Because of their experiences in the clue hunt, both kids are now more aware and more suspicious of what is going on around them. They are concerned when a guy on a motorbike follows Fiske and throws something at him. Fiske reassures the kids that the biker just wanted his parking spot and nothing more.
Later, the biker shows up at the house and is introduced as another Madrigal by the name of Erasmus. Fiske tells the kids the story of the ring that is in the care of the Madrigals and about the Vespers, a secret organization that recruits people who want power and are willing to do anything for the serum and ring. Fiske and Nellie are not ready for the kids to return to work on Cahill problems, but the ring is in danger and needs to be relocated. It is in a safety deposit box in Switzerland. The box requires Amy's and Fiske's signatures so it can be retrieved. They have been warned that the Vespers are on the rise and searching for the ring.
The kids travel with Fiske to Zurich and take a taxi through the city to the bank. Inside the box, they find a letter with a coded message that will help them find the ring and instructions from Grace that Amy is to be the next keeper of the ring. An alarm sounds, and a guard comes to help them get out of the bank safely. The guard's behavior and American accent make Dan suspicious and, with the help of Fiske and Amy, they overtake him and redirect the elevator to the top of the building.
They get off at the vice president's offices and report their story to him, complaining about the breach in security. The vice president does not believe them, and they are told to leave. Fiske takes the children to the family chalet, because of the letter's clues, where they dig the ring out of a loose brick in the fireplace. Amy notices blood coming out from under the closet door and looks up to the see the guard from the bank coming down the stairs. The children run while Fiske fights him.
The guard goes after the children on a foot chase, and Dan and Amy are able to get on a cable car just as the door is closing. A helicopter flies dangerously close to the cable car, and the kids recognize the pilot as one of the vice president's assistants at the bank. The helicopter cuts through one of the cables just as a police helicopter arrives to chase it away. A rescue helicopter is sent to get the people out of the cable car and down to safety.
Amy and Dan are told to wait for a rescue worker to take them down the hill but then recognize the worker as the guard from the bank. They grab a pair of skis and take off down the hill with two skiers chasing them. When Amy and Dan are caught, they are asked for the ring. Before they are able to make a move, a skier and snowboarder, Fiske and Erasmus, show up to their rescue. They all agree that the ring needs to be hidden, but Amy asks for it to be hidden out in the open. She has the ring converted into the face of a Swiss watch. When they return home, they agree to have Grace's home converted into a training facility that will prepare them physically and mentally for the day when the hunt starts again.