Obesity is one of the major risk factors of metabolic syndrome, such as hypertension, hyperlipidemia, and diabetes. Leptin exerts an anti-obesity effect through the Ob-Rb leptin receptor, which is mainly expressed on hypothalamic neuronal cells. Recent evidence indicated that one of the mechanisms of obesity may be the development of leptin resistance. In the present review, we discuss the mechanisms of leptin resistance in obesity, focusing on endoplasmic reticulum (ER) stress. We previously found that flurbiprofen is a candidate drug for attenuating ER stress and the subsequent development of leptin resistance. We will discuss a possible pharmacological strategy for treating obesity by ameliorating ER stress.