Barzini presided as head of one of New York's Five Families, and wielded power matched only by Vito Corleone. He had interests in markets such as narcotics, gambling and prostitution, and was also clever enough to be interested in Las Vegas and Nevada. Unlike Corleone, he was not considered a "Mustache Pete" and had a great deal of respect among younger Mafia leaders.
He was respected by his fellow Don enough to be invited to the wedding of Connie Corleone. However, when his counterpart refused to participate in the heroin trade, Barzini secretly conspired with the other families to make war with the Corleones, forcing them to make peace and open up their territory to drug trafficking. To this end, he approached Carlo Rizzi with a ploy to draw Sonny Corleone out to the tollbooth where he was ambushed and killed. Don Corleone, realizing this too late, agreed to lend his political protection to the enterprise and to never be the one to break the peace.
Not satisfied with the submission of the Corleones, Barzini began chipping away at their territory in New York City, and approached Corleone caporegime Salvatore Tessio to organize another peace summit where Vito's heir Michael Corleone would be ambushed. However, by this time the Don and his son had long anticipated Barzini's move and, on the day of the summit, he was assassinated along with the other conspirators. Corleone enforcer Al Neri, disguised as a police officer, shot the Don, his bodyguard, and his driver on the steps of the New York Supreme Court courthouse at Foley Square
In the 2006 video game, Barzini is the one who kills the protagonist's father "Johnny" causing the playable protagonist to seek revenge. In the game Don Barzini is killed on the court steps by the player who finally gets vengeance.
It is said that Emilio Barzini is loosely based on real-life mob boss Vito Genovese.