In recent years, genetic studies in humans have identified a handful of genes that are associated with common disorders, but our understanding of such diseases at the genetic level remains relatively rudimentary. The use of mice to dissect the complex genetic etiology of common disorders offers a viable alternative to human studies since experimental parameters, such as environmental influences, breeding scheme, and detailed phenotyping can be controlled. This review focuses on the utility of mouse genetics for identification of complex disease genes. Atherosclerosis is used as a representative example, followed by an overview for the prospects of successful gene discovery in the future.