The design of new therapeutic strategies for cancer treatment is based on the combination of drugs directed against different tumor compartments, including the tumor cells themselves and components of the stroma, such as the tumor vasculature. Indeed, several antiangiogenic compounds have entered clinical trials for use alone or in combination with conventional cytotoxic drugs. Pigment epithelium-derived factor (PEDF) is a multifunctional natural peptide with complex neurotrophic, neuroprotective, antiangiogenic, and proapoptotic biological activities, any of which could potentially be exploited for therapeutic purposes. This review summarizes recent studies that reveal the antitumor potential of PEDF based on its antiangiogenic properties and its newly discovered direct antitumor effects, which involve the induction of differentiation or apoptosis in tumor cells. We also discuss possible therapeutic applications of PEDF, based on these mechanistic insights and on the identification of functional domains that retain specific biological activities.