Heart failure can be a consequence of insufficient palliation of structural malformations in patients with congenital heart disease (CHD) or genetic perturbations resulting in cardiomyopathies. Although CHD is traditionally considered a pediatric clinical problem, there is a rapidly increasing population of patients surviving into adulthood with CHD and a corresponding increase in the rate of hospital admissions for adult CHD patients with heart failure. Therefore, there is recognition of the clinical importance in translating conventional heart failure pharmacotherapies to patients with CHD, improving management of heart failure in the context of structural consequences of CHD, and understanding the underlying genetic abnormalities which impact myocardial performance. Heart failure in CHD typically involves complex interactions between primary structural defects, the consequences of interventions (i.e., residual lesions), and the heart’s response to enhanced myocardial mechanical stress which depends on many other genetic factors (i.e., gene modifiers). In this review, we will examine how altered genes and hemodynamic loading contribute to heart failure seen in congenital heart patients. Understanding mechanisms of myocardial response and remodeling within the congenital population can provide insight into physiological principles and improve our understanding of heart failure.