Ceramide lipids have been implicated in the regulation of metabolic physiology. In particular, increased levels of the C-18 ceramide in muscle have been associated with impaired insulin action and increased visceral fat. Turner et al. identify the first isoform-selective ceramide synthase (CerS) inhibitor, P053, which specifically and potently targets CerS1 (responsible for C-18 ceramide formation), reducing C-18 ceramide levels in cultured cells and mouse skeletal muscle. In mice fed a high-fat diet, daily oral treatment with P053 promoted skeletal muscle fatty acid oxidation and reduced whole-body fat accumulation, without effects on insulin resistance.