Glucose transport and insulin resistance in the skeletal muscle of the genetically obese (ob/ob) mouse has been studied in animals at 6-7 wk of age using an in situ perfused hindquarter preparation. Rates of glucose uptake and the uptake of radioactively labeled 2-deoxy-D-glucose were lower in muscles from intact ob/ob mice than in those from their lean littermates. Following adrenalectomy the basal rate of glucose or 2-deoxy-D-glucose uptake in the ob/ob mice was restored to normal. The uptake of 2-deoxyglucose was tested at two insulin concentrations. In lean mice, adrenalectomy had no effect on 2-deoxyglucose uptake. Adrenalectomy, however, restored the responsiveness to insulin in the ob/ob mouse to normal. The activity ratio of muscle glycogen synthase was elevated by insulin but the effect was greater in the lean animals with or without adrenal glands than in the obese mouse. Adrenalectomy in the obese mouse did not correct this defect.