Santostefano was performing stand-up comedy in his hometown of Boston during his teens. While attending New York University Film School he began working professionally as a director, creating award-winning short films and documentaries. After college, Santostefano established a production company where he developed and directed film and television projects for HBO, Showtime, PBS and Paramount Television. He also directed several Off-Broadway stage productions including award-winning plays at The American Place Theatre. For the renowned BAM Festival (Brooklyn Academy of Music) he directed Stockhausen's contemporary opera "Leben."
Santostefano began a screenwriting career upon selling his first screenplay to Columbia Pictures and has continued writing and co-writing screenplays for several studios.