: Obesity is an epidemic, complex disease that is characterized by increased glucose, lipids, and low-grade inflammation in the circulation, among other factors. It creates the perfect scenario for the production of ceramide, the building block of the sphingolipid family of lipids, which is involved in metabolic disorders such as obesity, diabetes, and cardiovascular disease. In addition, obesity causes a decrease in fatty acid oxidation (FAO), which contributes to lipid accumulation within the cells, conferringmore susceptibility to cell dysfunction. C16:0 ceramide, a specific ceramide species, has been identified recently as the principal mediator of obesity-derived insulin resistance, impaired fatty acid oxidation, and hepatic steatosis. In this review, we have sought to cover the importance of the ceramide species and their metabolism, the main ceramide signaling pathways in obesity, and the link between C16:0 ceramide, FAO, and obesity.¿Fucho, R., Casals, N., Serra, D., Herrero, L. Ceramides and mitochondrial fatty acid oxidation in obesity. FASEB J. 31, 000-000 (2017). www.fasebj.org