A better understanding of the pathogenesis of distinct chronic obstructive pulmonary disease (COPD) phenotypes will improve diagnostic and therapeutic options for this common disease. We present evidence that sphingolipids such as ceramides are involved in the emphysema pathogenesis. Whereas distinct ceramide species cause cell death by apoptosis and necroptosis, cell adaptation leads to accumulation of other sphingolipid metabolites that extend cell survival by triggering autophagy. Cigarette smoke–released sphingolipids have been involved in both the initiation and persistence of lung injury via intracellular signaling and paracrine effects mediated via exosomes and plasma membrane–bound microparticles. Strategies to control sphingolipid metabolite production may promote cellular repair and maintenance to treat COPD.