The number and frequency of susceptibility alleles for common diseases are important factors to consider in the efficient design of disease association studies. These quantities are the results of the joint effects of mutation, genetic drift and selection. Hence, population genetics models, informed by empirical knowledge about patterns of disease variation, can be used to make predictions about the allelic architecture of common disease susceptibility and to gain an overall understanding about the evolutionary origins of such diseases. Equilibrium models and empirical studies suggest a role for both rare and common variants. In addition, increasing evidence points to changes in selective pressures on susceptibility genes for common diseases; these findings are likely to form the basis for further modeling studies.