Nectins are immunoglobulin-like cell adhesion molecules (CAMs) that compose a family of four members. Nectins homophilically and heterophilically interact in trans with each other to form cell-cell adhesions. In addition, they heterophilically interact in trans with other immunoglobulin-like CAMs. Nectins bind afadin, an actin filament (F-actin)-binding protein, at its cytoplasmic tail and associate with the actin cytoskeleton. Afadin additionally serves as an adaptor protein by further binding many scaffolding proteins and F-actin-binding proteins and contributes to the association of nectins with other cell-cell adhesion and intracellular signaling systems. Nectins and afadin play roles in the formation of a variety of cell-cell junctions cooperatively with, or independently of, cadherins. Cooperation between nectins and cadherins is required for the formation of cell-cell junctions; cadherins alone are not sufficient. Additionally, nectins regulate many other cellular activities (such as movement, proliferation, survival, differentiation, polarization, and the entry of viruses) in cooperation with other CAMs and cell surface membrane receptors.