<b><i>Background/Aims:</i></b> Obesity is a pervasive and highly prevalent disease that poses substantial health risks to those it affects. The rapid emergence of obesity as a global epidemic and the patterns and distributions of the condition within and between populations suggest that interactions between inherited biological factors (e.g. genes) and relevant environmental factors (e.g. diet and physical activity) may underlie the current obesity epidemic. <b><i>Methods:</i></b> We discuss the rationale for the assertion that gene × lifestyle interactions cause obesity, systematically appraise relevant literature, and consider knowledge gaps future studies might seek to bridge. <b><i>Results:</i></b> We identified >200 relevant studies, of which most are relatively small scale and few provide replication data. <b><i>Conclusion:</i></b> Although studies on gene × lifestyle interactions in obesity point toward the presence of such interactions, improved data standardization, appropriate pooling of data and resources, innovative study designs, and the application of powerful statistical methods will be required if translatable examples of gene × lifestyle interactions in obesity are to be identified. Future studies, of which most will be observational, should ideally be accompanied by appropriate replication data and, where possible, by analogous findings from experimental settings where clinically relevant traits (e.g. weight regain and weight cycling) are outcomes.