Non-insulin-dependent diabetes mellitus (NIDDM) constitutes about 85% of all cases of diabetes in developed countries and it has now reached epidemic proportions in many developing nations, as well as disadvantaged groups in developed countries, e.g., Mexican- and African-Americans and Australian Aborigines and Torres Strait Islanders. The diagnosis of NIDDM is usually made after the age of 50 years in Europids, but it is seen at much younger age in these high prevalence populations, which also include Pacific Islanders, Native Americans, and migrant Asian Indians and Chinese. There is enormous variation in NIDDM prevalence between populations, and exceptionally high rates have been documented in populations who have changed from a traditional to a modern lifestyle, e.g., American Pima Indians, Micronesians, and other Pacific Islanders, Australian Aborigines, migrant Asian Indians, and Mexican-Americans. Over the next decade, following the initial phase of the NIDDM epidemic, macro- and microvascular complications will emerge as a major threat to future public health throughout the world with huge economic and social costs. The major cause of death in NIDDM is macrovascular disease (coronary artery, peripheral vascular, and cerebrovascular), which accounts for at least two-thirds of NIDDM mortality. A key strategy in reducing macrovascular disease lies in the better understanding of the Deadly Quartet or Metabolic Syndrome. New data suggest that hyperleptinemia rather than hyperinsulinemia may play an important and central role in the genesis of the cardiovascular disease risk factor cluster that constitutes the Metabolic Syndrome.