Many intracellular stressors have been linked to insulin resistance, including lipids such as ceramides, mitochondrial reactive oxygen species, and Coenzyme Q. Whether these molecules cause insulin resistance independently or via some interconnected insulin resistance stress pathway is unknown. Here, we demonstrate a reciprocal relationship between ceramide and CoQ levels in mitochondria. Elevated mitochondrial ceramide in skeletal muscle cells results in CoQ depletion and insulin resistance, which can be reversed by CoQ supplementation. Conversely, decreasing mitochondrial ceramide increased CoQ levels in vitro and in animal models, protecting against insulin resistance. All these manipulations occurred independently of significant changes in proximal insulin-regulated signalling such as Akt phosphorylation. Collectively, these data indicate that this mitochondrial Ceramide-CoQ nexus may represent the foundation of a generic Insulin Resistance Stress Pathway that may play a critical role in other diseases associated with ceramide accumulation, including heart failure and cancer.