The incidence of obesity is increasing dramatically worldwide. In North America alone, approximately 60% of the population is either overweight or obese. Obese individuals are at high risk for the development of metabolic disorders, including insulin resistance, type II diabetes mellitus and cardiovascular diseases (CVD). In terms of CVD, in particular, obese individuals are at increased risk for heart diseases and stroke. Dyslipidemia in obesity is a major cause of obesityrelated CVD. More specifically, the characteristic dyslipidemia of obesity is elevated plasma triglycerides and low plasma levels of high-density lipoprotein (HDL) particles. Since HDL particles carry the “good cholesterol” and are highly anti-atherogenic particles, the lowering of plasma HDL levels in obesity, is of particular concern. Moreover, with every 1% increase in plasma HDL levels, there is a 1-3% decline in CVD risk. Thus, HDL rising in obesity is an attractive therapeutic target. However, because of its complex metabolism, developing safe and potent HDL raising therapies has been a challege. In terms of nonpharmacological therapies, diet and exercise interventions only raise plasma HDL levels modestly at best (10-15%). Of the current anti-obesity therapies, orlistat and sibutramine do not raise plasma HDL levels, while rimonabant does directly increase HDL concentrations. There is concern, however, over the serious central nervous system side-effects of rimonabant. Furthermore, in terms of HDL raising pharmaceutical therapies, the most widely used are niacin and fibrates. Fibrates only achieve a modest rise (10-15%) in plasma HDL, while niacin produces a larger increase (25%); however, due to the induction of flushing with niacin, it’s use is limited. More recently, non-flushing niacin has been developed which is a promising therapy. There is currently wide interest in developing new more potent HDL raising therapies that can induce greater reductions in CVD risk than current therapies. Foremost, the initially promising cholesteryl ester transfer protein (CETP) inhibitors proved to paradoxically increase CVD risk. In contrast, infusion of HDL or its protein apolipoprotein A-I has been more effective at reducing CVD risk. Overall, there are multiple points in the HDL metabolic pathway that may be targets for future HDL drug therapies and the future in HDL drug therapy holds great promise as we understand more about HDL’s complex physiology.