We have studied the pleiotropic effects of adrenomedullin with knockout mice and found that it is a potent intrinsic antioxidant. Oxidative stress is related to cardiovascular as well as metabolic diseases. In this review, the coronary, pulmonary, and cerebrovascular damage that was observed in adrenomedullin-knockout mice is reviewed. An angiotensin II-loaded model, a hypoxia model, and a vascular occlusion model were applied to investigate vascular damage, and the results clarified the role of oxidative stress and the therapeutic potency of adrenomedullin in vascular protection. From in vivo and in vitro studies, adrenomedullin is known to antagonize oxidative stress by both inhibiting nicotinamide adenine dinucleotide phosphate oxidase and promoting the degradation of oxidative stress. In addition, the role of adrenomedullin in insulin resistance and obesity is discussed based upon the results of both clinical studies and basic research studies that used aged adrenomedullin-knockout mice. The pleiotropic effects of adrenomedullin suggest a number of new therapeutic targets in a variety of diseases.