Despite advances in treatment over the past decade, heart failure remains a significant public health burden and a leading cause of death in the developed world. Gene therapy provides a promising approach for preventing and reversing cardiac abnormalities, however, clinical application has shown limited success to date. A substantial effort is being invested into the development of recombinant adeno-associated viruses (AAVs) for cardiac gene therapy as AAV gene therapy offers a high safety profile and provides sustained and efficient transgene expression following a once-off administration. Due to the physiological, anatomical and genetic similarities between large animals and humans, preclinical studies using large animal models for AAV gene therapy are crucial stepping stones between the laboratory and the clinic. Many molecular targets selected to treat heart failure using AAV gene therapy have been chosen because of their potential to regulate and restore cardiac contractility. Other genes targeted with AAV are involved with regulating angiogenesis, beta-adrenergic sensitivity, inflammation, physiological signalling and metabolism. While significant progress continues to be made in the field of AAV cardiac gene therapy, challenges remain in overcoming host neutralising antibodies, improving AAV vector cardiac-transduction efficiency and selectivity, and optimising the dose, route and method of delivery.