Atherosclerotic cardiovascular disease is the leading cause of morbidity and mortality in the developed countries. As a significant contributor to the development of atherosclerosis, the metabolic syndrome, consisting of obesity, type-2 diabetes mellitus, hypertriglyceridemia and hypertension, has become a major public health concern. Although insulin resistance has traditionally been considered a key factor in the metabolic syndrome, the precise mechanisms, which underlie the accelerated atherogenic processes have not been fully clarified. Over the past decade, adipose tissue has emerged as an important endocrine organ producing a variety of bioactive substances. These substances, termed adipocytokines, mediate many metabolic and inflammatory processes. Adiponectin is a novel and abundant adipose tissue-specific plasma protein. Visceral obesity, type-2 diabetes mellitus, hypertension and coronary artery disease are inversely related to adiponectin levels. Adiponectin-deficient mice exhibit all the features of the metabolic syndrome, and conversely, administration of adiponectin using adenovirus as a vector, reverses insulin resistance in these mice. Likewise, transgenic mice over expressing adiponectin ameliorated atherosclerotic lesion size in a mouse model of atherosclerosis. Adiponectin appears to be an anti-atherogenic substance: it accumulates within injured vascular walls and suppresses adherence of monocytes to endothelial cells; reduces uptake of oxidized low density lipoprotein (LDL) by macrophages thereby inhibiting foam cell formation and inhibits proliferation and migration of smooth muscle cells. These anti-atherogenic and anti-inflammatory properties of adiponectin seem to have promising therapeutic capabilities in the prevention and regression of atherosclerosis. The recent cloning of two adiponectin receptors (AdipoR1 and AdipoR2) will enable the identification of receptor distribution in specific tissues ultimately leading to a better understanding of the role of adiponectin in physiological and pathophysiological conditions. This review summarizes the role of adiponectin in protecting the vascular tree and outlines mechanisms by which adiponectin can be involved as a therapeutic target in the prevention and regression of vascular injury.