Human TNF-related apoptosis-inducing ligand (TRAIL) is a type II membrane protein that consists of 281 amino acids and shares 65% identity with the mouse protein (291 amino acids) at the amino acid level. The TRAIL extracellular domain can be cleaved to form a biologically active soluble form. TRAIL binds to two apoptosis-inducing receptors, TRAIL-R1 (DR4) and TRAIL-R2 (DR5), and two decoy receptors, TRAIL-R3 (LIT, DcR1) and TRAIL-R4 (TRUNDD, DcR2). In addition, TRAIL binds to osteoprotegerin (OPG), which is a soluble receptor. Once TRAIL binds to the R1 or R2, the apoptosis process begins with the receptor trimerization and formation of the death-inducing signaling complex (DISC). Subsequently, the Fas-associated death domain (FADD) translocates to the DISC, interacts with the death domain (DD) of the receptors, and recruits procaspases 8 and 10. TRAIL plays a key role in natural killer (NK) cell-mediated and IFNγ-dependent suppression of tumor cell growth. Also, TRAIL and CD95L participate in the regulation of T helper 1 (Th1) and T helper 2 (Th2) responses. There is a reciprocal expression of TRAIL and CD95L in Th1 and Th2 cells. In vitro-differentiated Th1 cells up-regulate CD95L, whereas Th2 cells express TRAIL. Th1 cells are more sensitive than Th2 cells to TRAIL-induced apoptosis, and c-FLIP, an anti-apoptotic regulator, seems to participate in this process. TRAIL targets cancer cells and is an attractive chemotherapeutic agent. Thus, recombinant human TRAIL variants, agonistic DR4, and DR5-specific antibodies are in preclinical development.