Ligands and receptors of the tumor necrosis factor (TNF) superfamily have pivotal roles in the development and function of the immune system. The growing pool of data on TNF from structural and biochemical studies suggests that the higher order clustering of TNF family ligands could play an essential role in signal transduction initiation for this superfamily. The identification of new structural modules of TNF family receptors, as well as interaction modes between ligands and receptors, greatly expands our knowledge of how TNF family ligands and receptors determine specificity among diverse family members and between two closely related family members.