The tumor necrosis factor (TNF) superfamily currently consists of 19 ligands and 29 receptors in humans, with three additional TNF superfamily receptors having been identified in mice. TNF-alpha and lymphotoxin-alpha, formerly known as TNF-beta, were the first members of the TNF superfamily to be identified. Most TNF ligands are type II transmembrane proteins whose extracellular domains can be cleaved by specific metalloproteinases to generate soluble cytokines. Receptors for TNF superfamily ligands are oligomeric, type I or type III transmembrane proteins. Several receptors for TNF superfamily ligands contain death domains (DDs) that recruit caspase-interacting proteins following ligand binding to initiate the extrinsic pathway of caspase activation. TNF superfamily ligands and receptors are important for normal developmental processes including apoptosis, regulation of immune cell functions, and additional cell type-specific responses. They also play a significant role in human disease including cancer and autoimmune diseases.