The immunogroblin (Ig) superfamily proteins characterized by the presence of Ig-like domains are involved in various cellular functions. The properties of the Ig-like domains to form rod-like structures and to bind specifically to other proteins make them ideal for cell surface receptors and cell adhesion molecules (CAMs). Ig-CAMs, nectins in mammals and Echinoid in Drosophila, are crucial components of cadherin-based adherens junctions in the epithelium. Nectins form cell-cell adhesion by their trans-interactions and recruit cadherins to the nectin-initiated cell-cell adhesion site to establish adherens junctions. Thereafter junction adhesion molecules, occludin, and claudins, are recruited to the apical side of adherens junctions to establish tight junctions. The recruitment of these molecules by nectins is mediated both by the direct and indirect interactions of afadin with many proteins, such as catenins, and zonula occludens proteins, and by the nectin-induced reorganization of the actin cytoskeleton. Nectins contribute to the formation of both homotypic and heterotypic types of cell-cell junctions, such as synapses in the brain, contacts between pigment and non-pigment cell layers of the ciliary epithelium in the eye, Sertoli cell-spermatid junctions in the testis, and sensory cells and supporting cells in the sensory organs. In addition, cis- and trans-interactions of nectins with various cell surface proteins, such as integrins, growth factor receptors, and nectin-like molecules (Necls) play important roles in the regulation of many cellular functions, such as cell polarization, movement, proliferation, differentiation, survival, and cell sorting. Furthermore, the Ig-CAMs are implicated in many human diseases including viral infections, ectodermal dysplasia, cancers, and Alzheimer's disease.