Heart disease remains the prevalent cause of premature death and accounts for a significant proportion of all hospital admissions. Molecular genetics was integrated quite late in cardiology, but introduced new concepts like sarcolemmopathies, cytoskeletalopathies, and channelopathies useful to better understand the pathophysiology of the development of inherited cardiomyopathies (CMs). As our understanding of the cellular and molecular processes involved in the development and progression of heart disease improved, new therapeutic targets were identified, as were novel approaches such as delivery of genes to replace defective or deficient components and thereby restore structure or function in a diseased heart. We discuss gene addition strategies in the context of monogenic disorders. Moreover, a broader nucleic acid-based modulation of cardiac gene expression for the treatment of cardiac diseases might have larger clinical indications. Inadequate gene delivery remains a potential cause of negative trials. However, progress in innovative formulations and clinically relevant ways of administration should lead to significant progress in the future. Cardiac gene therapy will be integrated into the therapeutic armamentarium for CM and heart failure.