Cell-cell adhesive processes are central to the physiology of multicellular organisms. A number of cell surface molecules contribute to cell-cell adhesion, and the dysfunction of adhesive processes underlies numerous developmental defects and inherited diseases. The nectins, a family of four immunoglobulin superfamily members (nectin-1 to -4), interact through their extracellular domains in a selective manner to support cell-cell adhesion. Our biochemical, structural and complementary mutagenesis studies reveal the basis for recognition and selectivity among the nectin family members. Of particular note, the close proximity of charged residues at the dimer interface is a major determinant of the binding affinities associated with homophilic and heterophilic interactions within the nectin family. Additionally, our biochemical and cell-based assays also establish a novel cross-talk between nectin and cadherin (another family of cell adhesion molecule).