There is a high potential for pharmacogenetic interaction in the management of many diseases including heart failure. Although genetic tailoring of therapy is not yet a common medical practice, it is foreseeable that some forms of genetic targeting will become standard care by the end of the current decade. This review will summary how genetic variation in two genes involved in both endothelial function and heart failure pathogenesis, angiotensin-converting enzyme and endothelial nitric oxide synthase, influence both heart failure outcomes and the effects of standard therapies.