Rimonabant is the first selective blocker of the cannabinoid-1 receptor in development for the treatment of obesity, diabetes mellitus, and cardiometabolic risk factors. (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.) Although it is associated with favorable effects on weight, waist circumference, serum lipids, C-reactive protein, and an improvement in glycemic control in type 2 diabetes, there are concerns about side effects. Generally, rimonabant has been well tolerated, with a primary side effect of nausea. Other side effects seen in trials have been anxiety and depressive symptoms, as well as neurologic events, albeit at low rates. When rimonabant becomes clinically available, physicians should be vigilant regarding the expected side effects and use alternative therapies if needed.