Massively parallel sequencing is emerging from research settings into clinical practice, helping the vision of precision medicine to become a reality. The most successful applications are using the tools of implementation science within the framework of the learning health-care system. This article examines the application of massively parallel sequencing to four clinical scenarios: pharmacogenomics, diagnostic testing, somatic testing for molecular tumor characterization, and population screening. For each application, it highlights an exemplar program to illustrate the enablers and challenges of implementation. International examples are also presented. These early lessons will allow other programs to account for these factors, helping to accelerate the implementation of precision medicine and health.