Intra-abdominal fat mass, or central adiposity, and cardiovascular risk are strongly correlated. Adipose tissue is an endocrine organ that secretes hormones and cytokines influencing appetite, energy metabolism, and atherosclerosis. National Heart, Lung, and Blood Institute (NHLBI) guidelines recommend that if dietary and lifestyle interventions fail to produce favorable outcomes in individuals with a body mass index >27 and weight-related comorbidities, as well as those with a body mass index >30, treatment plans may include weight loss medication. The endocannabinoid system has recently emerged as a viable target for the pharmacologic treatment of obesity and cardiometabolic risk factors. This article provides an in-depth review of efficacy results from clinical trials of rimonabant, a selective cannabinoid-1 receptor. (Recently, an FDA Advisory Committee recommended a delay in the approval of rimonabant because of safety issues that need to be addressed in further studies.) Compared with placebo, rimonabant 20 mg significantly decreased body weight and waist circumference measurements. In addition, rimonabant was associated with favorable changes in several other cardiometabolic risk factors, including significant increases in serum levels of high-density lipoprotein cholesterol and adiponectin, as well as reductions in serum levels of triglycerides, small, dense low-density lipoprotein particles, C-reactive protein, insulin resistance, and glycosylated hemoglobin.