The post-human genome sequencing era has presented several daunting challenges for biomedical research. How do we begin to quantify the level of sequence variation that exists within and between human populations? This challenge has serious implications for the enigma called “race,” genetic ancestry, group definition, and membership. Another challenge has been the attempt to understand the role DNA sequence variation contributes to variation in susceptibility to common complex diseases. How these challenges are met will have an impact on our ability to determine if health disparities (eg, cardiovascular disease) are due to biological differences. Here we discuss genetic variation among African Americans and Hispanic Americans and its implications for “race.” We believe that the casual use of “race” to define groups in biomedical research has contributed to our limited understanding of complex disease etiology and risk factors driving health disparities.