The present review focuses on the relationship between formation of N-acylethanolamine phospholipids (NAPEs) and N-acyletransferase (NAEs) catalyzed by N-acyltranferase and NAPE-hydrolyzing phospholipase D, respectively, and cell injury in tissues like brain, heart, and testis. A number of mechanisms are proposed by which these two groups of lipids may have cytoprotective properties. The mechanisms may involve activation of cannabinoid receptors, as well as non-receptor-mediated effects such as stabilization of membrane bilayers, antioxidant mechanisms, inhibition of calcium leakage from mitochondria, and direct inhibition of ceramidase. Anandamide (20:4-NAE) is formed as a minor component along with other NAEs during cell injury. Whether 20:4-NAE has a separate physiological role is at present not known, but some data suggest that 20:4-NAE may be formed, e.g. in the uterus, by a more selective mechanism without being accompanied by a vast majority of saturated and monounsaturated NAEs.