The extrinsic cell death pathway is initiated upon ligand-receptor interactions at the cell surface including FAS ligand-FAS/APO1, TNF-TNF receptors, and TRAIL-TRAIL receptors. Abnormalities of various components of these pathways have been identified in human cancer including loss of FAS expression, deletion or loss of TRAIL receptor DR4, mutation of TRAIL receptor DR5, overexpression of TRAIL decoy TRID or overexpression of Fas decoy, as well as overexpression of the caspase activation inhibitor, FLIP. Death ligands have been explored as potential therapeutics in cancer therapy with some limitations in the case of FAS and TNF due to toxicities. TRAIL remains promising as a therapeutic and has potential for combination with chemo- or radio-therapy. The death receptor signaling pathways include cross-talk with the mitochondrial pathway and can in some cases be influenced by mitochondrial membrane potential changes or NF-kappaB. FLIP and BCL-XL expression may reduce sensitivity of cancer cells to combination therapies.