In humans, insulin sensitivity is relatively impaired by diets that are low in oleic acid (OA), a cis monounsaturated fatty acid (MUFA), or rich in trans MUFA or palmitic acid (PA), a saturated fatty acid (FA). Emerging evidence exists that PA, in contrast to OA, causes insulin resistance via stimulation of inflammatory signaling and production of cytosolic lipid compounds (diacylglycerol and ceramide), leading one to presume that dietary or pharmacologic maneuvers that facilitate transport of FA into the mitochondria would be beneficial. However, in some models, insulin resistance is caused by excessive FA transport into the mitochondria, coupled with deficient electron transport and possibly increased reactive oxygen species formation; PA may impair electron transport via effects on gene expression. A research challenge is to determine whether feeding humans diets with markedly different contents of PA and OA would alter insulin sensitivity and/or critical biochemical mechanisms impacting muscle insulin signaling.