Serna's first break in movies came in 1970 on the Roger Corman directed film The Student Nurses. Over the years Serna has appeared in over 100 films, most notably Car Wash and Scarface directed by Brian De Palma, where he played Montana's friend Angel Fernandez (whose character was involved in the notorious "chainsaw scene"). In the award winning comedy Aguruphobia, Pepe plays the charismatic guru Nanak. Pepe co-produced Aguruphobia. Aguruphobia had a limited theatrical run, and is now available on iTunes, Amazon, Google Play and Verizon Fios. He has also appeared on stage, including his solo show El Ruco, Chuco, Cholo, Pachuco which is Serna's version of the panorama of Latino cultural history.