Caveolin-3 is expressed predominantly in skeletal muscle fibers where it drives caveolae formation at the muscle cell's plasma membrane (sarcolemma). From in vitro studies, it has been suggested that caveolin-3 may play a positive role in insulin signaling and energy metabolism. In this study, we directly address the in vivo metabolic consequences of genetic ablation of caveolin-3 in mice as it relates to insulin action, glucose metabolism, and lipid homeostasis. Interestingly, we note that at two months of age, Cav-3 (-/-) null mice are significantly larger than wild-type mice, exhibiting increased whole-body and abdominal adiposity. Furthermore, Cav-3 null mice display significant post-prandial hyperinsulinemia, whole-body insulin resistance, and whole-body glucose intolerance. Studies using hyperinsulinemic-euglycemic clamps revealed that Cav-3 null mice exhibited 20% and 40% decreases in insulin-stimulated whole-body glucose uptake and whole-body glycogen synthesis, respectively. Whole-body insulin resistance was mostly attributed to 20% and 40% decreases in insulin-stimulated glucose uptake and glucose metabolic flux in the skeletal muscle of Cav-3 null mice. In addition, insulin-mediated suppression of hepatic glucose production was significantly reduced in Cav-3 null mice, indicating hepatic insulin resistance. Surprisingly, insulin-stimulated glucose uptake in white adipose tissue (WAT), which does not express caveolin-3, was decreased by ~70% in the Cav-3 null mice, suggestive of an insulin resistant state for this tissue. During fasting, Cav-3 null mice possess normal insulin receptor protein levels in their skeletal muscle. However, after 15 minutes of acute insulin-stimulation, Cav-3 null mice show dramatically reduced levels of the insulin receptor protein, as compared with wild-type mice treated identically. Mechanistically, these results suggest that caveolin-3 normally functions to increase the stability of the insulin receptor at the plasma membrane, preventing its rapid degradation, i.e., by blocking or slowing ligand-induced receptor down-regulation. Thus, our results demonstrate the importance of caveolin-3 in regulating whole-body glucose homeostasis in vivo and its possible role in the development of insulin resistance. These findings may have clinical implications for the early diagnosis and treatment of Caveolinopathies, such as LGMD-1C, or related muscular dystrophies.