Pharmacotherapy remains the cornerstone in the treatment of heart failure. There is a wide variability in the individual's response to treatment, which is at least partially ascribed to genetic factors. Pharmacogenetics studies the differential clinical effects due to genetic variances. Some effects of the major neurohormonal inhibitors like angiotensin-converting enzyme (ACE)-inhibitors and beta-blockers are importantly modulated by genetic polymorphisms. So far, however, this does not result in standard genetic testing before starting specific therapy. This review discusses several important pharmacogenetic targets. Furthermore, it is argued that new and sophisticated high-throughput genetic screens could be employed to develop pharmacogenetic screening further. Prospective large-scale pharmacogenetic studies are warranted as we believe that they will identify new targets for therapy and specific populations that benefit from specific treatments.