Obesity has been recognized to increase the risk of such diseases as cardiovascular diseases, diabetes, and cancer. It indicates that obesity can impact genome stability. Oxidative stress and inflammation, commonly occurring in obesity, can induce DNA damage and inhibit DNA repair mechanisms. Accumulation of DNA damage can lead to an enhanced mutation rate and can alter gene expression resulting in disturbances in cell metabolism. Obesity-associated DNA damage can promote cancer growth by favoring cancer cell proliferation and migration, and resistance to apoptosis. Estimation of the DNA damage and/or disturbances in DNA repair could be potentially useful in the risk assessment and prevention of obesity-associated metabolic disorders as well as cancers. DNA damage in people with obesity appears to be reversible and both weight loss and improvement of dietary habits and diet composition can affect genome stability.