Pigment epithelium-derived factor (PEDF) is one of the serine protease inhibitors with multifunctional properties, which is produced by various types of organs and tissues. There is an accumulating body of evidence that PEDF plays an important role in the maintenance of tissue homeostasis. Indeed, PEDF not only works as an endogenous inhibitor of angiogenesis, but also suppresses oxidative stress, inflammatory and thrombotic reactions in cell culture systems, animal models, and humans. Furthermore, we, along with others, have found that PEDF inhibits proliferation of, and induces apoptotic cell death in, numerous kinds of tumors. In addition, circulating as well as tumor expression levels of PEDF have been inversely associated with tumor growth and metastasis. These observations suggest that supplementation of PEDF proteins and/or enhancement of endogenous PEDF expression could be a novel therapeutic strategy for the treatment of cancer. Therefore, in this paper, we review the effects of PEDF on diverse types of cancer, and discuss its therapeutic perspectives.