Phospholipase D (PLD) has emerged as a regulator of several critical aspects of cell physiology. PLD, which catalyzes the hydrolysis of phosphatidylcholine (PC) to phosphatidic acid (PA) and choline, is activated in response to stimulators of vesicle transport, endocytosis, exocytosis, cell migration, and mitosis. Dysregulation of these cell biological processes occurs in the development of a variety of human tumors. It has now been observed that there are abnormalities in PLD expression and activity in many human cancers. In this review, evidence is summarized implicating PLD as a critical regulator of cell proliferation, survival signaling, cell transformation, and tumor progression.