Background: Cardiac gene therapy is approaching reality, with clinical trials entering Phase II/III. Even so, challenges exist to improve the efficacy of even the most successful therapies. Objective: The merits of different gene therapy vectors are weighed to assess the current feasibility of each in specific cardiac applications. Major obstacles are discussed, along with recent advances in vector development to overcome or circumvent those difficulties. Methods: This review focuses primarily on gene delivery via naked DNA, adenovirus, lentivirus, and adeno-associated virus (AAV) vectors. Conclusion: Gene therapy via adenovirus and AAV vectors has developed into a promising option for the treatment of heart disease. The merits of gene therapy compared with emerging stem cell and microRNA-based treatments are discussed.