It is a well-known fact that severe obesity is associated with the metabolic syndrome, type 2 diabetes, cardiovascular disease, hypertension, and other diseases. Epidemiological studies have suggested that obesity is also associated with increased risk of several cancer types. The number of people who are suffering from severe obesity is growing, and clinical data suggest that severely obese patients belong to a unique population with regards to risk, efficacy of screening, and cancer treatment. This review will point out the potential mechanism linking obesity and cancer and will discuss several challenges in various treatment modalities of cancer in obese patients.