Overweight and obesity have been rising dramatically worldwide and are associated with numerous co-morbidities such as cardiovascular disease (CVD), type 2 diabetes mellitus, hypertension, certain cancers, and sleep apnea. In fact, obesity is an independent risk factor for CVD and CVD risks have also been documented in obese children. The majority of overweight and obese patients who achieve a significant short-term weight loss do not maintain their lower bodyweight in the long term. This may be due to a lack of intensive counseling and support from a facilitating environment including dedicated healthcare professionals such as nutritionists, kinesiologists, and behavior specialists. As a result, there has been a considerable focus on the role of adjunctive therapy such as pharmacotherapy for long-term weight loss and weight maintenance. Beyond an unfavorable risk factor profile, overweight and obesity also impact upon heart structure and function. Since the beginning, the quest for weight loss drugs has encountered warnings from regulatory agencies and the withdrawal from the market of efficient but unsafe medications. Fenfluramine was withdrawn from the market because of unacceptable pulmonary and cardiac adverse effects. Nevertheless, there is extensive research directed at the development of new anti-obesity compounds. The effect of these molecules on CVD risk factors has been studied and reported but information regarding their impact on the cardiovascular system is sparse. Thus, instead of looking at the benefit of weight loss on metabolism and risk factor management, this article discusses the impact of weight loss medications on the cardiovascular system. The potential interaction of available and potential new weight loss drugs with heart function and structure is reviewed.