Epidemiological studies have demonstrated that the prevalence of chronic diseases such as diabetes, cardiovascular diseases, and certain types of cancers are mainly induced by body weight gain and obesity. It is recognized that excess calorie intake and reduced physical activity are the fundamental causes for weight gain and obesity, among which dietary lipids have been correlated with increases in body mass index. An increasing attention has focused on dietary lipids, both quantity and quality, to prevent the development of obesity. The first part of this article introduces the contemporary understanding of dietary lipids in weight gain and obesity, including the transcriptional factors, namely, sterol regulatory element-binding proteins (SREBPs) and peroxisome proliferator-activated receptors (PPARs), involved in fatty acids metabolism. The second part reviews the role of overweight and obesity in chronic diseases, with focus on the underlying mechanism of obesity-induced inflammation, type 2 diabetes, cardiovascular diseases, and cancers.