Alveolar cell apoptosis is a critical element of experimental and human emphysema, in that it accounts for alveolar destruction and interacts with oxidative stress, inflammation, and protease activation, all contributing to the unique nature of the disease. Prompted by our finding of up-regulated ceramide levels in lungs of patients with smoking-induced emphysema (1), we demonstrate that ceramide, a second messenger lipid, is a critical mediator and amplifier of alveolar cell apoptosis in experimental emphysema. Inhibition of enzymes of the de novo ceramide synthesis prevented lung ceramide increases, alveolar cell apoptosis, oxidative stress, and emphysema caused by blockade of vascular endothelial growth factor receptor (VEGFR) with SU5416 in both rats and mice. The lung alterations seen with VEGFR blockade were reproduced with intratracheal instillation of ceramide in naive mice. Furthermore, reduction of lung levels of very long ceramides after administration of a neutralizing ceramide antibody in vivo and the inability of acid sphingomyelinase–deficient fibroblasts to augment endogenous ceramide synthesis in response to exogenous ceramide indicated a feed-forward mechanism of ceramide regulation mediated via the secretory acid sphingomyelinase. Finally, the finding that supplementation of sphingosine-1-phosphate (S1-P) prevented lung cell apoptosis due to VEGFR blockade suggests that ceramide–S1-P balance might be critical in the maintenance of alveolar septal integrity. We have therefore identified ceramide as a critical pathogenetic element in emphysema and a promising target for pharmacologic intervention in a disease with no available therapies.