The use of racial variables in genetic studies has become a matter of intense public debate, with implications for research design and translation into practice. Using research on smoking as a springboard, the authors examine the history of racial categories, current research practices, and arguments for and against using race variables in genetic analyses. The authors argue that the sociopolitical constructs appropriate for monitoring health disparities are not appropriate for use in genetic studies investigating the etiology of complex diseases. More powerful methods for addressing population structure exist, and race variables are unacceptable as gross proxies for numerous social/environmental factors that disproportionately affect minority populations. The authors conclude with recommendations for genetic researchers and policymakers, aimed at facilitating better science and producing new knowledge useful for reducing health disparities.