The American Recovery and Reinvestment Act has provided resources for comparative effectiveness research that will lead to evidence-based decisions about health and health care choices. Some have voiced concerns that evidence-based comparative effectiveness research principles are only relevant to "average" patients and not as much to individuals with unique combinations of genes, exposures and disease outcomes, intrinsic to genomic medicine. In this commentary, we argue that comparative effectiveness research and genomic medicine not only can and should coexist but also they will increasingly benefit from each other. The promise and success of genomic medicine will depend on rigorous comparative effectiveness research to compare outcomes for genome-based applications in practice to traditional non-genome-based approaches. In addition, the success of comparative effectiveness research will depend on developing new methods and clinical research infrastructures to integrate genome-based personalized perspectives into point of care decisions by patients and providers. There is a need to heal the apparent schism between genomic medicine and comparative effectiveness research to enhance knowledge-driven practice of medicine in the 21st century.