Obesity is a chronic disease that is increasing at epidemic proportions. Our research group has been studying skeletal muscle metabolism in severely obese patients for more than 25 yr. These studies were possible initially because of collaborating surgeons providing abdominal muscle (rectus abdominus) biopsies that were examined in muscle strip preparations. These in vitro incubation studies were complimented with experiments using needle biopsies of a leg muscle (vastus lateralis) and skeletal muscle cell cultures derived from the tissue of lean and severely obese donors (11, 26). In these preparations, we have observed a consistent metabolic profile in severely obese individuals (body mass index (BMI), Q40 kgImY2), which has led us to hypothesize that a constitutive ‘‘obesity metabolic program’’that contributes to a positive lipid balance and insulin resistance is involved. This review will focus on our findings implicating the existence of a metabolic program in skeletal muscles of severely obese individuals.