The CD38 antigen displays restricted functional associations with surface molecules involved in immune system and complement. Capping of the CD38 molecule in normal or neoplastic T cells is followed by rapid and specific co-modulation of the CD3-T cell receptor (TcR) complex. In normal and tumor cells of B lineage, CD38 was found to be also associated with surface Ig (sIg) and with the complement receptor 2 (CR2)/CD19 complex. The CD38 molecule expressed by purified natural killer cells displayed an association with the low affinity IgG Fc receptor (Fc gamma RIII) CD16. These observations suggest that specialized areas in the plasma membrane contain co-modulating structures, including different receptors involved in the transduction of extracellular signals. We propose a model whereby TcR, CR2 and CD16 are ligand binding structures in their respective lineages, while CD38 is a molecule involved in the intracellular transduction of the signals.