The recent increase in the proportion of the population with obesity and/or type 2 diabetes is a matter of great concern for global public health. The rising incidence of these disorders is clearly attributable to changes in the environment that promote caloric consumption and decrease energy expenditure. However we need to understand why some individuals are susceptible to obesogenic influences while others remain resistant. Similarly, it would be helpful to have a better insight into the mechanises whereby some seriously obese people completely avoid the metabolic consequences of over-nutrition while others succumb to the disabling complications of metabolic derangement despite being only modestly obese. In this lecture I will describe how human genetics has helped to enhance our understanding of our susceptibility or resistance to obesity and its adverse metabolic consequences. The findings have broad-ranging implications for the management of individual patients, for drug development and for public health strategies.