Activation of cell surface death receptors by their cognate ligands triggers apoptosis. Several human death receptors (Fas, TNF-R1, TRAMP, DR4, DR5, DR6, EDA-R and NGF-R) have been identified. The most promising cytokine for anticancer therapy is TRAIL/APO-2L, which induces apoptosis in cancer cells by binding to death receptors TRAIL-R1/DR4 and TRAIL-R2/DR5. The cytotoxic activity of TRAIL is relatively selective to cancer cells compared to normal cells. Signaling by TRAIL and its receptors is tightly regulated process essential for key physiological functions in a variety of organs, as well as the maintenance of immune homeostasis. Despite early promising results, recent studies have identified several TRAIL-resistant cancer cells of various origins. Based on molecular analysis of death-receptor signaling pathways several new approaches have been developed to increase the efficacy of TRAIL. Resistance of cancer cells to TRAIL appears to occur through the modulation of various molecular targets. They may include differential expression of death receptors, constitutively active Akt and NFkappaB, overexpression of cFLIP and IAPs, mutations in Bax and Bak genes, and defects in the release of mitochondrial proteins in resistant cells. Conventional chemotherapeutic and chemopreventive drugs, and irradiation can sensitize TRAIL-resistant cells to undergo apoptosis. Thus, these agents enhance the therapeutic potential of TRAIL in TRAIL-sensitive cells and sensitize TRAIL-resistant cells. TRAIL and TRAIL-receptor antibodies may prove to be useful for cancer therapy, either alone or in association with conventional approaches such as chemotherapy or radiation therapy. This review discusses intracellular mechanisms of TRAIL resistance and various approaches that can be taken to sensitize TRAIL-resistant cancer cells.