Overnutrition manifested by obesity has emerged as a major health problem in affluent countries. In spite of increased interest in fitness, obesity is on the increase in the United States. This is particularly so among children and adolescents. Although obesity is associated with many risk factors for diseases, the mechanisms whereby it enhnaces disease risk are not fully understood. Such an understanding is needed to develop strategies for management of these conditions. In this report we suggest that over-nutrition produces clinical disease only in individuals who already possess a metabolic weakness or “defect” in a given system. In the absence of such underlying defects, overnutrition, or obesity, is well tolerated. One of the most common consequences of obesity is dyslipidemia, that is, elevations of very low-density lipoprotein (VLDL) triglycerides and low-density liproprotein (LDL) cholesterol and low concentrations of high-density lipoprotein (HDL) cholesterol. The major effect of overnutrition on lipoprotein metabolism is to stimulate the production of VLDL. For patients who have an underlying defect in lypolysis of VLDL triglycerides, hypertriglyceridemia will develop in the obese state. For those who have defective clearance of LDL, obesity will accentuate hypercholesterolemia. Both of these effects can be explained by overproduction of VLDL, due to obesity, combined with a genetic defect in clearance of VLDL or LDL. The mechanism whereby obesity causes a lowering of HDL cholesterol is uncertain, although it could enhance removal of HDL by an excess of adipose tissue. Another disease associated with obesity is cholesterol gallstones. The presence of obesity more than doubles the risk for gallstones. Two underlying factors increase the danger for gallstones: a deficiency of hepatic secretion of bile acids and a tendency for formation of cholesterol crystals in bile. Overnutrition promotes the synthesis of whole-body cholesterol, and the only route for excretion of this excess cholesterol is thorugh the biliary tree. Thus obesity leads to an increased output of cholesterol in bile. When this response is combined with either a deficiency of bile acids or a propensity to crystal formation, the risk for gallstones is greatly raised. A high incidence of obesity among patients with non-insulin-dependent diabetes mellitus (NIDDM) is well known. It appears that obesity is not the underlying cause of NIDDM, but when combined with a primary defect in insulin metabolism, NIDDM develops. Most likely, the primary defect in most patients with NIDDM is a progressive decline in ability to secrete insulin by beta cells of pancreatic islets. In contrast, the major effect of obesity on glucose metabolism is to heighten resistance ot the peripheral action of insulin. When obesity is combined with a defect in secretion of insulin, hyperglycemia develops more readily. Another adverse effect of overnutrition may be increased hepatic secretion of glucose, which likewise could worsen glucose tolerance. Finally, some NIDDM patients may have a primary insulin resistance, which is worsened in the presence of obesity. Approximately 50% of patients with “essential” hypertension are obese, and overnutrition no doubt contributes to elevated blood pressure. The mechanisms whereby obesity raises blood pressure are not fully understood. Since many obese people do not have hypertension, there must be underlying defects in blood pressure control for hypertension to become manifest in obese individuals. Obesity appears to increase plasma volume and to enhance cardiac output. When this effect is combined with a primary increase in peripheral vascular resistance, the rise in blood pressure is accentuated. However, obesity also may raise peripheral vascular resistance by producing hyperinsulinemia, which may impair sodium excretion and accentuate peripheral resistance. Finally, limited data suggest that overnutrition increases the risk for certain types of cancer, namely, breast, colon, and prostate cancer. If so, it seemingly is a promoter of cancer development rather than a primary initiator. Still, epidemiologic and experimental data are insufficient to conclude that obesity definitely is a risk factor for human cancer. In summary, overnutrition and obesity have major impacts on metabolism in many body systems. When these are combined with inherent metabolic defects, disease states may be induced. In the absence of obesity, such defects may be well tolerated by many people. From a practical point of view, there is the need for a careful evaluation of all obese patients for the presence of these diseases or risk factors. Otherwise, with failure to detect and modify these abnormalities, adverse health consequences may ensue over the course of the next few years.