Sphingomyelin hydrolysis and ceramide generation have emerged as key events in cellular regulation. Sphingomyelinases (SMases) catalyse the breakdown of sphingomyelin to form ceramide and phosphorylcholine. Ceramide formed through activation of SMases may function as a second messenger in mediating cell growth, differentiation, stress responses, and programmed cell death (apoptosis). So far, five types of SMases have been described and they include the acidic, the acidic zinc-dependent, the neutral magnesium-dependent, the neutral magnesium-independent, and the alkaline SMase. These SMases differ in tissue distribution, cofactor dependence, mechanism for regulation, and involvement in diverse cellular processes. At least two of these sphingomyelinases may regulate the intracellular levels of ceramide and subsequent ceramide-mediated responses. This review will focus on the identification, regulation and roles of SMases in cell function.