Heart failure is a heterogeneous disease, the development and pathophysiology of which involves complex interactions between genetic and environmental factors. It is well known that there are several heritable forms of heart failure in which genetic variation makes an individual more likely to develop the disease; however, less is clear about the degree to which genetics plays a role in the pathogenesis of more classic forms of heart failure. Several studies have been performed in patients with heart failure to determine the influence of modifier genes on exercise capacity, cardiovascular and pulmonary function, and outcomes, including survival. Given the variability in the response to pharmacologic treatment in patients with heart failure, there is an emerging interest in the optimal pharmacologic intervention for a given genotype in patients with heart failure. This review focuses primarily on several modifier genes, principally those associated with regulation of the adrenergic and rennin-angiotensin-aldosterone systems and those important to vascular control in heart failure, as well as the impact of these genes in the response to treatment.