Human CD38 is the mammalian prototype of a family of proteins which share structural similarities and an ectoenzymatic activity involved in the production of calcium mobilizing compounds. Besides the enzymatic activity, the molecule performs as a receptor, ruling adhesion and signaling in leukocytes. These functions are exerted through the interaction with surface ligands, one of which was identified as CD31. Recently, CD38 has gained attention as a prognostic marker and a pathogenetic agent in leukemias and in other diseases. Together these insights have produced a model of an as yet unique family of molecules, which act independently as receptors and enzymes.