As a cellular signaling program, apoptosis is a highly controlled and complex process that depends on the orchestrated interactions of multiple soluble factors: ions (e.g., Ca2+), proteins (e.g., caspases, Bcl-2 family members), and nonprotein substrates (e.g., DNA). Equally important, although less well characterized, is signaling through cellular membranes and the lipids and proteins contained therein. Lipids are the primary constituents of biological membranes and thus play a structural role in defining cellular and organellar boundaries. However, lipids are not merely passive molecules serving inert, structural functions in these membranes. Many lipids are now appreciated as signaling molecules, capable of influencing diverse cellular processes and exerting powerful influence over many physiologic and pathophysiologic processes, such as programmed cell death. Sphingolipids represent one class of bioactive lipid mediators that are now recognized as key determinants of cell fate. This chapter discusses the regulated generation of bioactive sphingolipids (e.g., ceramide) and how sphingolipid signaling impacts the regulation of programmed cell death.