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The Ishbal War began around the year 1900 when a special ops team from Ametris infiltrated the city and killed several locals. The people of Ishbal revolted and the Amestrisian military began a full scale assault on the region. According to Dr. Marcoh’s accounts, the resulting wave of violence "lasted seven years, until the Führer had had enough". Tired of the endless conflict in the region, King Bradley ordered a brigade of State Alchemists, led by then-Colonel Basque Grand, into Ishbal to end the war once and for all. After a futile attempt at defending their homeland, the surviving Ishbalans fled, only to be attacked by State Alchemists such as Grand and Zolf Kimblee. The remaining refugees were rounded up and relocated to concentration camps.

In the manga, the war begins after a child is shot by Envy, disguised as an Amestrisian soldier. A rebellion began, and Amestris sent in the military to put it down. Although the Amestrisian military was superior to the Ishbalan rebellion's forces, the rebels held out quite well against the military, killing many Amestrisian soldiers. It was decided that the powerful State Alchemists were to be used, and they were dispatched to the region. The Ishbalan annihilation campaign began, using the Alchemists as a key tool in murdering Ishbalan civilians as well as ending the rebellion. Although the leader of the Rebellion attempted to make a truce with the Führer by sacrificing himself in return for the sparing of the remaining Ishbalans, the Führer did not comply and continued the campaign, demonstrating that the war had escalated into a full-scale genocide, akin to that of the Holocaust.