Heart failure management is complex and costly. Genetic variations that alter drug absorption, metabolism, and receptor-ligand interactions have the potential to modify drug response and safety. Evidence shows that genetic factors interact with numerous heart failure medications, including vasodilators, beta blockers, and angiotensin-converting enzyme inhibitors. Technologic advances will soon allow population-based genome-wide genetic testing at a reasonable cost. Understanding the genetic factors that influence drug response in heart failure will allow physicians to personalize therapies and optimize response while minimizing serious adverse events.