Western populations have a growing obesity epidemic due in part to excessive nutrient intake from high-fat diets, which are increasingly common. Overindulgence of nutrients is associated with a greater incidence of metabolic dysfunction and a greater risk for obesity, diabetes, hypertension, and other metabolic disorders that lower quality of life. Research in humans and animal models has improved our understanding of how excess circulating free fatty acids negatively impact the ability of muscle and other tissues to regulate nutrient uptake and utilization. It is generally accepted by the scientific community that excess circulating fatty acids lead to insulin resistance, but there is little clarity regarding the underlying mechanisms. In the present review, we will outline the current understanding of the characteristics associated with fatty acid mobilization and fatty acid utilization within specific tissues. We will also discuss the potential mechanistic role of hyperlipidemia on metabolic dysfunction associated with type 2 diabetes.