Cannabinoids, the active components of Cannabis sativa (marijuana), and their endogenous counterparts exert their effects by binding to specific G(i/o)-protein-coupled receptors that modulate adenylyl cyclase, ion channels and extracellular signal-regulated kinases. Recent research has shown that the CB(1) cannabinoid receptor is coupled to the generation of the lipid second messenger ceramide via two different pathways: sphingomyelin hydrolysis, and ceramide synthesis de novo. Ceramide in turn mediates cannabinoid-induced apoptosis, as shown by in vitro and in vivo studies. These findings provide a new perspective on how cannabinoids act, and raise exciting physiological and therapeutic questions.