The initial draft sequence of the human genome, published in 2001, promised to usher the world towards personalized medicine, in which a patient’s genome is used to diagnosis, treat, and prevent illness. Almost twenty years later, many clinically actionable mutations have been identified and are incorporated into treatment, and medical genomics offers exciting opportunities for data-driven discoveries about the genomic underpinnings of health. As increasingly large genomic datasets merged with medical records become available to researchers and the public turns to direct-to-consumer companies for genomic analysis, challenging humanistic issues surrounding privacy, preexisting conditions, ancestry, and kinship abound. As a human population geneticist, I study the evolutionary forces that produce and maintain genetic variation in our species. I’ll describe a series of fundamental challenges for interpreting results from direct-to-consumer genetic testing and for making personalized medicine a reality for all.