Obesity is growing at an alarming rate with huge consequences on health and economy. The worldwide prevalence of obesity has nearly doubled in less than 35 years. Obesity causes many physiological dysfunctions that affect nearly every organ producing multiple morbidities. Despite these facts, there is still no clear, well-defined solution. Notwithstanding the devastating prevalence and consequences of obesity, today only five medicines, orlistat, lorcaserin, phentermine-topiramate, bupropion-naltrexone and liraglutide, are approved by the FDA for long-term treatment of obesity. In this review, the current approaches to treat obesity such as the development of diacylglycerol Oacyltransferase- 1 inhibitors, growth hormone secretagogue receptor-1a antagonists/inverse agonists, melanocortin-3 receptors agonists and melanin concentrating hormone receptor-1 antagonists, will be discussed. The main focus will be on the molecules that were able to reach clinical trials. The last section is dedicated to the "browning" phenomenon of white adipose tissues and the potential of Aldh1a1 inhibitors to treat obesity.