Pharmacogenomics is a growing field of research that focuses on how an individual's genetic background influences his or her response to therapy with a drug or device. Increasing evidence from clinical trials in patients with heart failure (HF) due to systolic dysfunction suggests that genetic variations can predict the occurrence of HF, influence the effects of standard therapies, and influence outcomes of HF patients. This article reviews the underlying principles of pharmacogenomics, discusses some of the complex variables that influence the investigational approach to pharmacogenomics, demonstrates how variations in genes encoding a variety of different proteins can influence the effects of pharmacologic agents, and describes the potential impact of pharmacogenomics on the treatment of patients with HF.