Abstract Receptors in the nerve growth factor/tumor necrosis factor receptor family are characterized by the presence of cysteine-rich motifs of ~40 amino acids in the extracellular domain. The ligands are type II transmembrane proteins with β-strands that form a jelly-roll β-sandwich. The receptors recognize soluble or cell-surface-bound ligands and mediate diverse cellular responses. Activation of intracellular signals is mediated at least in part by the association of proteins with a RING finger motif or a death domain to the cytoplasmic domains of the receptors. In addition to cell-membrane-bound receptors soluble forms have been described for most of the receptors. Activation of intracellular signals not only occurs through ligand binding to the receptors but cross-linking of at least some members of the ligand family can regulate cell functions.