The promise of "personalized medicine" guided by an understanding of each individual's genome has been fostered by increasingly powerful and economical methods to acquire clinically relevant information. We describe the operational implementation of prospective genotyping linked to an advanced clinical decision-support system to guide individualized health care in a large academic health center. This approach to personalized medicine entails engagement between patient and health-care provider, identification of relevant genetic variations for implementation, assay reliability, point-of-care decision support, and necessary institutional investments. In one year, approximately 3,000 patients, most of whom were scheduled for cardiac catheterization, were genotyped on a multiplexed platform that included genotyping for CYP2C19 variants that modulate response to the widely used antiplatelet drug clopidogrel. These data are deposited into the electronic medical record (EMR), and point-of-care decision support is deployed when clopidogrel is prescribed for those with variant genotypes. The establishment of programs such as this is a first step toward implementing and evaluating strategies for personalized medicine.