Specificity of gap junction formation produces communication compartments, groups of cells joined to each other by gap junctions (homologous communication) but more rarely to cells in adjacent compartments (heterologous communication). Specificity of junction formation can be studied in mixed cultures of different cell types. In these model systems, compartmentation is often associated with sorting out, a process that produces separate domains of the different cells. The borders of the physically distinct domains correlate with the functional boundaries of the communication compartments. Compartments have also been observedin vivowhere they are believed to play a role in separating groups of cells following different differentiation pathways. Two classes of cell surface molecule, connexins and cell adhesion molecules, are candidates for a role in the control of specificity. A representative of each class appears to be necessary for gap junction formation and both are expressed in a tissue specific manner. We have shown that mixed cultures of rat epithelial (BRL) cells and rat (BICR) fibroblasts show specificity, form communication compartments and sort out. Both cell types express the same connexin (connexin 43) but different cell adhesion molecules (BRL, P-cadherin and 125-kDa N-cadherin; BICR, 140-kDa N-cadherin). Transfection of both cell types with E-cadherin results in a 10-fold increase in heterologous communication. These data suggest that E-cadherin plays a role in the control of specificity of gap junction formation.