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Obesity is a worldwide epidemic with rates nearly doubling over the last 30 years. Despite increasing prevalence, the multifactorial pathogenesis of obesity continues to be widely misunderstood. Investigating genetic drivers in the development of obesity is an important area of focus, as genetics move to the forefront of medicine and personalized treatment evolves. Thus, this narrative review focused on four genes which have genome-wide association study–documented links to obesity and obesity syndromes. We explored their involvement in the predisposition, progression, and prognosis of obesity. Leptin, leptin receptor, pro-opiomelanocortin, and melanocortin 4 receptor are our four genes of interest, and herein we elaborated on the current literature, pathogenesis, and available treatments for patients with these specific genetic mutations.