The global epidemic of obesity is rapidly accelerating in both industrialized and developing countries, and has raised significant healthcare concerns worldwide. Obesity leads to numerous co-morbidities, including cardiovascular diseases (CVD), type 2 diabetes (T2D), hypertension, certain cancers, and sleep apnea. Obesity is considered an independent risk factor for CVD, and is associated with dyslipidemia, hypertension, glucose intolerance and inflammatory markers; all of which contribute to CV risk. The benefits of weight reduction to decrease cardiometabolic risk are well-documented, yet long term weight loss has been difficult to achieve. This has lead to intense efforts within the pharmaceutical industry to develop agents that result in weight loss and prevent weight regain. Numerous strategies have been directed toward decreasing food intake and/or increasing energy expenditure, yet this has met with limited success in developing a safe and effective drug. This review summarizes the underlying mechanisms contributing to CV risk in obesity, and discusses the targets that may result in novel pharmacological agents that can sustain weight loss and reduce cardio-vascular morbidity and mortality.