Medicine has long sought to match diagnostic and treatment approaches to the particular needs and risks of individual patients. The decreasing cost and increasing ease of genetic sequencing have propelled the rise of precision medicine. Precision medicine aims to use genetic and other information to provide care tailored to the individual patient, with the goal of improving clinical outcomes and minimizing unnecessary diagnostic and therapeutic interventions. Although developments in genetic sequencing have the potential to transform clinical care, there are important limitations, including uncertainty in the clinical interpretation of many genetic variants and concerns about privacy, discrimination, and cost. To help clinicians understand the basics of genetic sequencing and how to apply it in clinical practice, Annals of Internal Medicine is launching a new "Precision Medicine" series. This introduction provides a general overview of clinical sequencing, with a focus on germline variation. Subsequent articles will use a case-based format to provide concise summaries of specific clinical precision medicine scenarios that are relevant to the practice of internal medicine. These cases will highlight specific clinical indications; interpretation of genetic test results; and ethical, legal, cost, and privacy issues related to genetic testing. The goal is to provide practical information on the appropriate application and interpretation of genomics in routine clinical practice.