Lifestyle intervention programs including increased physical activity and healthy nutrition have been proven to delay the onset of type 2 diabetes. This is achieved mainly by reducing body weight and improving insulin sensitivity. However, response to lifestyle or dietary interventions does differ between individuals, and the genetic or environmental factors that may account for these differences are not yet precisely characterized. Identification of these factors would be desirable in order to provide an individually tailored preventive strategy for patients at risk of developing diabetes. This review summarizes the so far known genetic variations, which determine responders and nonresponders to a lifestyle intervention. In addition, general methodological approaches to study gene–lifestyle interactions are described.