Summary:  There is a genetic basis to the most common immune-mediated diseases. Identifying disease susceptibility genes, however, has been a challenge. Only a few genes have been consistently replicated across multiple studies. These convincing examples provide insight into a genetic approach to common immune diseases as well as insight into disease pathogenesis. Here, we discuss several important concepts of a genetic study – patterns, power, and proof – and why these are germane in testing inherited variation for influence on disease. Recent developments in the fields of human genetics and genomics are overcoming limitations within the field, and we anticipate many exciting discoveries in the near future.