Background: Heart failure (HF) and multiple HF-related phenotypes are heritable. Genes implicated in the HF pathophysiology would be expected to influence the response to treatment. Methods: We conducted a series of systematic literature searches on the pharmacogenetics of HF therapy to assess the current knowledge on this field. Results: Existing data related to HF pharmacogenomics are still limited. The ADRB1 gene is a likely candidate to predict response to β-blockers. Moreover, the cytochrome P450 2D6 coding gene (CYP2D6) clearly affects the pharmacokinetics of metoprolol, although the clinical impact of this association remains to be established. Conclusion: Given the rising prevalence of HF and related costs, a more personalized use of HF drugs could have a remarkable benefit for patients, caregivers and healthcare systems.