Skeletal muscle is a primary regulator of glucose homeostasis, accounting for the majority of post-prandial glucose disposal. However states of skeletal muscle insulin-resistance result in severely attenuated glucose uptake and consequently hyperglycemia. The underlying cause of insulin-resistance in obese populations is currently theorized to be the consequence of lipotoxicity, but as of yet the intramyocellular mechanisms for this response remain elusive. Lipid intermediates such as diacylglycerol possess a high affinity for ligand binding/activation of protein kinase C (PKC) isoforms. PKC isoform θ specifically, has a strong correlation with lipid accumulation and insulin-stimulated glucose uptake inhibition. In order to investigate PKCθ’s role in skeletal muscle insulin-resistance, a muscle specific PKCθ knock out mouse model was employed followed by a 15 week high fat diet. The phenotype exhibited by our skeletal muscle PKCθ knock out mice is one of reduced weight gain, lipid accumulation, inflammation, and insulin resistance compared to wild type controls. The immunity to such deleterious effects regularly witnessed in high fat fed wild type mice further illustrates the prominent manner by which PKCθ induces skeletal muscle insulin-resistance.