Eleven years since the initial drafts of the human genome were published, we have begun to see the first examples of the application of whole-genome sequencing to personalized diagnosis and therapeutics. The exponential decline in sequencing costs and the constant improvement in these technologies promise to further advance the use of a patient's full genetic profile in the clinic. However, realizing the potential benefit of such sequencing will require a concerted effort by science, medicine, law, and management. In this review, we discuss current approaches to decoding the 6 billion-letter genetic code of a whole genome in a clinical context, give current examples of translating this information into therapy-guiding knowledge, and list the challenges that will need to be surmounted before these powerful data can be fully exploited to forward the goals of personalized medicine.