TNF superfamily ligands and receptors are critical mediators of multiple physiological processes. Several TNF superfamily members regulate immune cell functions including B cell homeostasis and activation, T cell co-stimulation, and natural killer cell regulation. A number of TNF superfamily receptors contain intracellular death domains (DDs) through which they can initiate the extrinsic pathway of caspase activation. Other TNF superfamily members that lack DDs can also initiate apoptosis via indirect mechanisms. In addition to mediating immune cell functions and apoptosis, select TNF superfamily members regulate additional cell type-specific responses.