Obesity is one of the most common chronic conditions in the world. Its management is difficult, partly due to the multiple associated comorbidities including fatty liver, diabetes, hypertension, and hyperlipidemia. As a result, the choice of prescription medications in overweight and obese patients has important implications as some of them can actually worsen the fat accumulation and its associated metabolic complications. Several prescription medications are associated with weight gain with mechanisms that are often poorly understood and under-recognized. Even less data are available on the distribution of fat and lipotoxicity (the organ damage related to fat accumulation). The present review will discuss the drugs associated with weight gain, their mechanism of action, and the magnitude and timing of their effect.