The cadherin superfamily plays key roles in intercellular adhesion. An emerging intercellular adhesion system, consisting of nectin and afadin, also has roles in organization of a variety of intercellular junctions either in cooperation with, or independently of, cadherin. Nectin is a Ca(2+)-independent immunoglobulin-like intercellular adhesion molecule, and afadin is a nectin- and actin-filament-binding protein that connects nectin to the actin cytoskeleton. This novel intercellular adhesion system has roles in the organization of E-cadherin-based adherens junctions and claudin-based tight junctions in epithelial cells. The adhesion system is furthermore involved in the formation of synapses in neurons and the organization of heterotypic junctions between Sertoli cells and spermatids in the testis.