Abstract: Cellular Fas-associated death domain-like interleukin-1 β-converting enzyme inhibitory protein (c-FLIP) belongs to the death effector domain superfamily, which is important in regulating apoptosis and proliferation. c-FLIP inhibits the extrinsic receptor-mediated apoptotic pathways and intrinsic mitochondrial apoptotic pathways through competition with caspase-8 for recruitment to Fas-associated death domain protein. Moreover, the cleavage products (i.e., p43-FLIP fragment and p22-FLIP fragment) directly activate NF-κΒ, Erk survival signaling, and other non-apoptotic signaling pathways. The c-FLIP (L) can function either as an anti-apoptotic molecule, in a way analogous to c-FLIP (S) and c-FLIP (R), or as a pro-apoptotic molecule to facilitate the activation of caspase-8 at the death-induced signaling complex. The identified dual functionality of c-FLIP depends on various factors, including its expression level, interaction with caspase-8, and its subcellular localization. c-FLIP is frequently over-expressed in many different tumor types, and contributes to tumor cell immune surveillance, chemotherapy resistance, and apoptosis-resistance induced by TNFα, TRAIL, and FasL. Furthermore, c-FLIP is essential in obtaining aggressive biological behaviors, and is useful in predicting the prognosis of patients with various malignant tumors. This review focuses on the molecular mechanisms that control the dual regulation of c-FLIP in life/death decision at death-induced signaling complex. Increasing evidence supports the function of c-FLIP as a tumor therapeutic marker to restore an apoptotic response for TRAIL therapy in cancers. Insight into these processes will improve our understanding of apoptosis, and provide new approaches for rational treatment strategies.