Missanelli attended Pennsylvania State University (Penn State), where he played college baseball as a second baseman for the Penn State Nittany Lions. He graduated from Penn State in 1977. He is also a 1986 graduate of the Delaware Law School of Widener University at the same time he was working for the Philadelphia Inquirer.
Born and raised in Bristol, Pennsylvania, Missanelli began his career there as a newspaper writer, working at the Philadelphia Inquirer and eventually moved over to radio working on-air at 610 WIP and 93.3 WMMR. Missanelli joined WPHL-TV in 2000 where he worked as sports director and anchor. He left the station in 2003 when his contract expired. In January 2010, he signed a new multi-year deal at ESPN affiliate, 97.5 The Fanatic. He was fired from 610 WIP in January 2003 and began a show with Joe Conklin on WMMR. Missanelli is also a professor at Saint Joseph's University.
Missanelli has repeatedly battled the perceptions of Philadelphia fans, as he himself has written, "Let me assure that when I tear into a guest, like Michael Wilbon or a Skip Bayless or a Keith Law, it's for a good reason that has absolutely nothing to do with me personally and everything to do with having the backs of the people, who have had to tread the filthy water of Philly fan perception, fostered by lazy national media nitwits, way too long."