As magic little pills go, the weight-loss drug rimonabant was destined to be huge. It was supposed to put a dent in the obesity epidemic and help people quit smoking and improve their cholesterol along the way. Pharmaceutical execs expected it to usher in a new class of drugs bigger than cholesterol-controlling statins, like Lipitor, Pfizer’s $1-billion-a-month blockbuster. Such was the promise when rimonabant hit Europe in 2006 under the brand name Acomplia.

But the drug never made it to American medicine cabinets. Doctors soon realized that rimonabant exacerbated already high rates of anxiety, depression and suicidal thinking among the obese. Last fall, manufacturer Sanofi-Aventis pulled Acomplia from shelves after five people from a trial of 36,000 patients taking it committed suicide (as did one person taking a placebo). The company abandoned the drug, and concerns about the compound’s safety led Merck and Pfizer to dump their copycat versions, both in late-stage trials. “The class as a whole is defunct,” says Nick Turner, an industry analyst with Mirabaud Securities, an investment firm that tracks pharmaceuticals.

Now doctors are back to square one, with precious few medicinal options for the two thirds of Americans who are overweight. For the one third who are obese, the situation is dire. Obesity, defined as having a body-mass index of 30 or greater, sets the stage for diabetes and killer conditions such as heart disease, stroke and cancer. Aside from advice (stop eating) and stomach surgery for the severely obese (say, 5-foot-8, 265 pounds), there are just two anti-obesity medications approved for long-term use, and the pounds come right back on as soon as you stop taking them. The appetite suppressant sibutramine, a non-addicting cousin of amphetamines, can increase blood pressure in an already hypertensive population, and the fat blocker orlistat (sold over the counter as Alli) can cause what doctors call “fecal urgency” and diarrhea. Worse, both produce only marginal weight loss. “That’s the real killer,” says Steve Bloom, who heads the metabolic-medicine department at Imperial College London. “The reality is, we seem to be getting nowhere.”

The same reasons it’s hard for most people to slim down in any permanent fashion through diet and exercise account for the fact that we still don’t have an anti-obesity drug that’s safe, effective and tolerable. But there is hope in the pipeline. A handful of candidates stand to deliver weight-loss figures big enough to improve not just health but body image, a key to getting patients to stay with the treatment. Bear in mind, the studies are still small—usually only several hundred volunteers—and short, meaning there isn’t enough statistical power to spot potentially dangerous side effects. So we’re not picking any winners here. But they all control appetite surprisingly well, and they do it through very different methods, so it may not be one pill that keeps us thin but a cocktail of them. “I think the future is going to be about hitting multiple pathways with multiple agents,” says Ken Fujioka, director of nutrition and metabolic research at the Scripps Clinic Center for Weight Management in La Jolla, California.