Genes underlie numerous human diseases and traits. Although we have witnessed a great deal of success in identifying disease-susceptible genes, the task remains challenging for most of the complex diseases. This paper reviews evidence for the role of genetic factors in complex diseases including breast cancer, diabetes and multiple sclerosis. We then describe strategies that can potentially optimize our chance of success in identifying genes involved in complex diseases. Advances in molecular biology, particularly mapping of the human genome, statistical methods that provide more accurate models of complex patterns of inheritance, and basic medical science, which have increased our understanding of disease pathophysiology, will ultimately strengthen the ability of the current generation of genetic epidemiological studies to identify the genetic basis of complex human disorders.