To determine whether a defect in insulin binding could contribute to insulin resistance in Egyptian sand rats (Psammomys obesus), insulin binding to isolated hepatocytes from euglycemic sand rats was compared to that of normal Sprague-Dawley rats (Rattus norvegicus). Because of its potential importance in glucoregulation, glucagon binding to hepatocytes from these species was also measured. Hepatocytes of sand rats exhibit an almost complete lack of insulin receptors compared to hepatocytes from Sprague-Dawley rats, whereas there are numerous high affinity glucagon binding sites on sand rat hepatocytes. The lack of insulin binding to sand rat tissues is sufficient to entirely explain the insulin resistance seen in this species. Glucagon may be primarily responsible for glucose homeostasis in Psammomys obesus.