Death receptors belong to the tumor necrosis factor receptor superfamily and can induce apoptosis through activation of procaspase-8. The cellular FLICE-inhibitory protein (c-FLIP) is able to modulate activation of procaspase-8 and thereby prevents induction of apoptosis mediated by death receptors. As an important modulator of caspase-8, c-FLIP regulates life and death in various types of normal cells and tissues, such as lymphoid cells, and renders resistance to death receptor-mediated apoptosis in many types of cancer cells. In addition to an apoptosis modulator, c-FLIP has been shown to exert other physiological functions related to cell proliferation and tumorigenesis. Dysregulation of c-FLIP expression has been shown to be associated with various diseases, such as cancer and autoimmune diseases, and c-FLIP might be a critical target for therapeutic intervention. This review focuses on recent findings about the physiological function and intracellular regulation of c-FLIP.