The combination of angiotensin-converting enzyme (ACE) inhibitors and β-adrenergic receptor (βAR) blockers remains the essential component of heart failure (HF) pharmacotherapy. However, individual patient responses to these pharmacotherapies vary widely. The variability in response cannot be explained entirely by clinical characteristics, and genetic variation may play a role. The purpose of this chapter is to examine the current knowledge in the field of beta-blocker and ACE inhibitor pharmacogenetics in HF. β-blocker and ACE inhibitor pharmacogenetic studies performed in patients with HF were identified from the PubMed database from 1966 to July 2011. Thirty beta-blocker and 10 ACE inhibitor pharmacogenetic studies in patients with HF were identified.The ACE deletion variant was associated with greater survival benefit from ACE inhibitors and beta-blockers compared with the ACE insertion. Ser49 in the β1AR, the insertion in the α2CAR, and Gln41 in G protein-coupled receptor (GPCR) kinase (GRK)-5 are associated with greater survival benefit from β-blockers, compared with Gly49, the deletion, and Leu41, respectively. However, many of these associations have not been validated. The HF pharmacogenetic literature is still in its very early stages, but there are promising candidate genetic variants that may identify which HF patients are most likely to benefit from beta-blockers and ACE inhibitors and patients that may require additional therapies.