The first half of the anime's plot adapts the first seven volumes of the manga, but then the plots severely diverge from each other by the middle of the story, specifically around the time where Roy Mustang's friend Maes Hughes is murdered by the homunculus Envy in disguise. Dante, a former lover of Hohenheim and mentor to the Elric brothers' teacher, is the series' central antagonist. Centuries ago, Hohenheim and Dante perfected methods for making the Philosopher's Stone and achieved immortality by transferring their souls and intellects into other bodies as they age. Hohenheim was eventually overcome with the guilt of sacrificing lives to make the Stone and left Dante. Although Dante can still jump from body to body with the last stone she and Hohenheim created, she is not willing to risk the rebound of creating one herself. She thus uses the homunculi to encourage Edward and Alphonse, along with other equally desperate Alchemists to create another complete Philosopher's Stone for her.
When Scar creates the Philosopher's Stone, at the cost of his life as well as the lives of 7,000 soldiers, he infuses it into Alphonse's metal body, which leads to Alphonse's kidnapping. Edward goes and tries to rescue him, but is killed by Envy. Alphonse uses the Philosopher's Stone to revive his brother but disappears in the process. Dante tries to escape but she is killed when the homunculus Gluttony, whose mind she had earlier destroyed, fails to recognize his master. After being revived, Edward risks his life to bring back his brother and finds himself in a parallel world, while Alphonse recovers his original body. Determined to reunite with Alphonse, Edward becomes involved in rocketry research, intending to use that technology to return to his home world. The story concludes in the film adaptation Conqueror of Shamballa, in which Edward's search attracts the attention of the Thule Society, which seeks to enter his homeworld—believing it to be Shamballa—to obtain new weapons to help them in World War II. Dietlinde Eckhart, a member of the Thule Society, enters the other world and tries to destroy Amestris. She is defeated by the Elric brothers, who decide to stay in Germany.