The story of Fullmetal Alchemist: Brotherhood closely follows Hiromu Arakawa's original Fullmetal Alchemist manga, a tightly plotted narrative with themes ranging from mankind's dual nature to conspiracy, war crimes, revenge, forgiveness, destiny and more.
Many scenes in this acclaimed series are important either because they move the plot along with an exciting (or horrifying) turn of events, and/or they reveal shocking new information that clears up crucial details. It's tricky to narrow down this complex plot to five turns of events, but these are arguably the most impactful and compelling plot twists of them all.
Edward & Alphonse Attempt To Transmute Their Mother's Soul
This is the event that kicked off the entire Fullmetal Alchemist story from a narrative standpoint (but not a chronological one). The Elric brothers loved their mother Trisha. After she died, the brothers resolved to use their gifts in alchemy and science to bring her back to life. This was a forbidden art for a reason, and when the brothers fired up their transmutation circle, they realized something had gone wrong. Alchemy is based on equivalent exchange, and nothing can equal the human soul in value. They effectively tried to steal from God and lost parts of their bodies as punishment. That launched their entire quest to find the Philosopher's Stone, and it also gave the brothers a new, humbler perspective on alchemy and the Truth itself.
The Dwarf In The Flask Recruits Slave #23
This plot twist was not the first to be shown in the anime, but it did take place first chronologically. A few centuries ago, the desert city-state of Xerxes was home to the mysterious "dwarf in the flask," and young slave #23 soon befriended it. The tiny, strange homunculus promised the slave power via alchemy and even gave him a name: Van Hohenheim. Hohenheim soon bought his freedom and learned much about alchemy and transmutation circles, and the two friends made an offer to the Xerxes King himself.
A giant transmutation circle would supposedly grant the king immortality, but instead, every single Xerxian citizen was sacrificed to create a giant Philosopher's Stone to turn the dwarf into a powerful entity -- and Hohenheim got a piece of that power. Father the homunculus was born, and with this humanoid body he could take the next big step in his grand plan to become a god. He soon created seven sons and daughters too, including the shadowy Pride who resembled him.
Edward & Alphonse Learn How Philosopher's Stones Are Made
Early in the series, Edward and Alphonse got a solid lead on the Philosopher's Stone, with Dr. Tim Marcoh (the Stone's inventor) guiding them to his research notes. Once the destroyed notes were reconstructed with Sheska's help, the Elric brothers finally cracked the tough code and realized what they were seeing. The Philosopher's Stone was made from sacrificing countless human lives. Worse yet, the Amestris government and military complex were both routinely making these things from Ishvalans and prisoners.
Edward and Alphonse immediately resolved to never use these Stones for their own good, setting the tone for the entire series. This is why Dr. Marcoh feels so incredibly guilty for what he's done, and it explains why Scar the vengeful monk hates the doctor so much.
Envy Launches The Ishval Civil War
This plot twist impacted the Fullmetal Alchemist tale more than once, including the war itself and the later revelation of Envy's role in it. Father's grand plan required many sacrifices, and he sent Envy the shapeshifter to set off a spark in the tense Ishval situation. Envy assumed the form of an Amestris soldier and shot an innocent child dead, setting off a bloody civil war that the Ishvalans ultimately lost.
The countless casualties indeed fueled Father's plan, explaining why Scar is so determined to assassinate every state alchemist he can find. Roy Mustang later learned the truth from Envy himself, and in retaliation for that and Maes Hughes' death, Roy took the fight to Envy without mercy.
The Discovery Of Father's Giant Transmutation Circle
Edward and Alphonse journeyed north to the massive Fort Briggs in time for another major insight into Father's plan. Ed and his allies realized that Sloth the homunculus had dug a tunnel right under Fort Briggs, which was part of a massive underground circle underneath the entire nation of Amestris. Now with the world's largest transmutation circle, Father could sacrifice everyone in Amestris to become a true god.
But that's not all. Ed also realized that every bloody event in Amestris' history, such as border wars and civil wars, all took place at strategic spots on that huge transmutation circle. The Ishval Civil War was the most recent such event, and soon after, a bloody border clash with Drachma would serve as the final ingredient in the circle's completion.
Armed with this knowledge, Ed and his allies could take the fight to Father more effectively and shut down his hidden plan before it could come to full fruition. Scar's brother's research also depicted this transmutation circle, along with a way to counteract it.