The sphingomyelin (SM) pathway is an ubiquitous, evolutionarily conserved signaling system, analogous to conventional systems such as the cAMP and phosphoinositide pathways. Ceramide is generated from SM by the action of a neutral or acid SMase, or by de novo synthesis coordinated through the enzyme ceramide synthase. Once generated, ceramide may serve as a second messenger in signaling responses to physiologic or environmental stimuli, or may be converted to a variety of structural or effector molecules. In the radiation response, ceramide serves as a second messenger in initiating apoptosis, while some of its metabolites block apoptosis. In certain cells, such as endothelial, lymphoid and haematopoietic cells, ceramide mediates apoptosis while in others ceramide may serve only as a co-signal for or play no role in the death response. Regulated ceramide metabolism may determine the balance between pro- and anti-apoptotic signals, and hence, the intensity of the apoptotic response, thus constituting a mechanism of radiation sensitivity or resistance. This paradigm may offer new opportunities for modulation of the radiation effects in the treatment of cancer. Chemical modifiers of ceramide metabolism may be useful to enhance the therapeutic effects or reduce the toxicity of radiation treatment.