Mafia don Vinnie Salerno made his presence known in 2003, after fellow mobster Danny Santos had finally accomplished his task of leaving the "family business." With the powerful Santos family out of business, Springfield was now ripe territory and Salerno made his presence known. To convey a message to Danny that he was back, Vinnie sent thugs to go after the people he cared about, namely Danny's cousin, Tony Santos, and their business partner, Cassie. Finally having had enough, Danny met with Vinnie in New York and made him a deal--he'd give him the Santos's illegal operations in exchange for Salerno staying out of Springfield. That same summer, Salerno would have dealings with another Springfield citizen--Eden August. Eden was once an employee of Salerno's in New York City and was now running an escort service in Springfield. At this time, Eden was a suspect in a series of murders connected to her escort service and, with help from Tony, went to Salerno for help in getting an alibi. For old time's sake, he obliged but made it very clear to Eden that she owed him. Not long after, in an effort to get drive Eden away from Tony, Salerno sent Eden photos of Tony abusing a woman. Unfortunately, the plan didn't work. Meanwhile, one day, Eden phoned Salerno telling him that she wanted to go back to her old life. Going on the rooftop to meet with her, Salerno found Tony instead and realized that he'd been set up. When Tony nearly threw Salerno off the roof, Vinnie admitted the photos were fake, but continued to provoke Tony. Luckily for Vinnie, Tony let him go.

A few months later, Salerno visited Danny who was running for mayor of Springfield. Although Vinnie offered to lend his financial support to Danny's campaign, Danny refused; a move did not make Salerno happy. So, in 2004, Salerno was justifiably suspicious when Danny (who had been forced to concede the election amid allegations of fraud) asked to come work for him. Danny was quickly able to convince Salerno that he was disillusioned and that he wanted back into his former life. At the same time, Vinnie was looking to collect his debt on Eden, now engaged to the upstanding Bill Lewis. Vinnie ended up harassing Eden for weeks by sending notes, flowers, and merely being in the same room with her and staring. His interest in Eden didn't go unnoticed by Bill, who foolhardily warned Vinnie to stay away. Angry at Bill's attitude, Vinnie wanted to teach him a lesson but was dissuaded by Danny. Soon after, Vinnie finally told Eden what he wanted--Salerno was expecting a drug shipment, Antimonious, and wanted her to intercept it and bring it to him. However, instead of giving the drugs to Salerno, Eden flushed them down the toilet! Infuriated, Vinnie placed a hit on Eden and ordered Danny to take care of it. However, Vinnie was still uncertain as to whether or not Danny was up to the task, and had Tony trail Danny. To his satisfaction, Danny apparently completed his assignment by luring Eden to an abandoned warehouse and detonating a bomb.

Soon after, when Danny demonstrated his loyalty to his boss by foiling a police raid, Salerno rewarded him by finally giving him the coveted job of playing bagman to his San Cristobel Antomonious supplier. Although he made plans to be out of Springfield when the drop went down, he was curtailed by the arrival of resident psychic Reva Lewis who convinced him that traveling at this time would be a bad idea. Although skeptical at first, Vinnie was, at heart, a superstitious man and when some of Reva's predictions came true, Salerno decided to stay put. Unfortunately, that would prove to be his undoing. The night of the drop off, as Vinnie commandeered Reva at the San Cristobel gala and tried to persuade her, using threats, to be his own personal psychic, a Federal sting was going on. Just as the drugs were given to Salerno, the cops burst in. Vinnie suddenly realized he'd been set up – and Danny was in on it! He knocked out Danny and dragged Reva outside, using her as a shield. But Reva played mind games, convincing Salerno that she sensed that his gun has no bullets and therefore she was just going to walk away. Though Vinnie didn't buy this, he was unnerved long enough for Danny to fly out the door and take him down. Later in prison, Salerno got two unexpected visitors. The first was Detective Gus Aitoro who, unsuccessfully, tried to get Vinnie to sign a false confession stating that he was trying to frame the Chief of Police and the second was an interview with Reva, in which Danny's wife, Michelle, learned that Danny set the explosion in the warehouse that left her with amnesia.

In 2007, Josh Lewis was convicted for the attempted murder of Alan Spaulding. Shortly after arriving in prison, he was attacked by a pair of Salerno's men. The beatings went on for several days and Reva believed they were because she was the one who got Salerno put in jail. Vinnie confirmed it himself to Josh days later. To the dismay of the Lewis family, the attacks continued. Eventually, the only viable solution was to keep Josh in solitary confinement, which he had trouble adjusting to. Luckily for Josh, his confinement ended after less than a month when someone else confessed to the crime.