Recently we showed that fructose feeding in rats induced nonproteolytic activation of prorenin and subsequent angiotensin II production in skeletal muscle. In addition, a pharmacological inhibitor of prorenin/(pro)renin receptor interaction attenuated the development of insulin resistance. However, the inhibitor did not ameliorate the glucose intolerance in transgenic rats overexpressing the human renin gene. This review article summarizes the current knowledge of the effects of the prorenin/(pro)renin receptor system on insulin resistance and its potential as a therapeutic target.