Apoptosis, a form of cell death that is coordinated by a set of defined biochemical pathways, exists throughout the animal kingdom. Its critically important roles in development, homeostasis, and disease have made this a topic of intensive research and sometimes even more intensive controversy. One of these areas of controversy concerns the role of ceramide, produced by the hydrolysis of sphingomyelin. In this issue, Tepper et al.(2000) add to this debate with an interesting new theory. When we consider the central mechanisms of apoptosis, we have two general questions to ask: first, what determines whether a cell will live or die? And if a cell is to die, what determines the precise form of this cell death? The second question is often as important as the first, as we’ll see.

Evidence from early experiments showed that ceramide is produced under a variety of conditions leading to apoptosis (Kolesnick and Kronke, 1998). The knowledge that synthetic ceramide was able to induce apoptosis, led to the unfortunately too simple conclusion that the production and action of ceramide is an obligatory step in the apoptotic process. Therefore, several studies (based predominantly on correlations) put forth the idea that sphingomyelin hydrolysis and signaling via ceramide are essential in the decision of whether a cell dies. This conclusion fell from favor as evidence accumulated against ceramide production as a major determinant of the life/death decision. Now, a new study by Tepper and colleagues in this issue (Tepper et al., 2000) has perhaps defined a new role for sphingomyelin hydrolysis in apoptosis, determining not whether but how a cell dies. To understand this role in the context of the apoptotic process (as it is currently understood), we will first review the process itself and examine the different roles that have been proposed for sphingomyelin hydrolysis in the different pathways to apoptotic cell death. When cells die via apoptosis, they undergo a number of morphological and biochemical changes that are stereotypical for this type of death. These changes are orchestrated by a set of cysteine proteinases that become active during apoptosis, the caspases (cysteine proteinases with specificity for aspartic acid residues; reviewed in Wolf and Green, 1999). The final throes of cell death (and the associated changes) have been named execution and the caspases responsible for coordinating these changes are