Ceramide, an intracellular lipid mediator, is generated by transient hydrolysis of sphingomyelin in response to agonists inducing inflammation and apoptosis, ionizing radiation, chemotherapeutics or ischaemia/reperfusion. An elevated intracellular ceramide production is predominantly induced by an elevated hydrolytic activity of sphingomyelinases or by the activity of enzymes controlling de novo synthesis, such as ceramide synthase. Ceramide is implicated in various cellular responses, acting as an autonomous intracellular effector in cell cycle regulation, differentiation, senescence, and apoptosis. Furthermore, by changing membrane properties it contributes to the assembly and interactions of various signal transduction molecules. The lipid mediator is subsequently metabolised by ceramidase and sphingosine kinase, and other key players, which determine the dynamic balance between the intracellular levels of ceramide and its breakdown products (the ceramide/S1P rheostat). Together with sphingomyelinases, they are crucial for cell signalling, cellular survival or initiation of apoptosis. Sphingomyelinases are regarded as key enzymes in the regulated activation of the sphingomyelin cycle. Up to now, five isoforms of sphingomyelinases are known, differentiated by agonists, intracellular localization, pH optimum and essential co-factors. Herein, we focus on the biochemical background and the action of pharmacologically interesting compounds capable of interfering with sphingomyelinases and outline their potential implications for medicinal chemistry.