Heart transplantation for end-stage heart failure is an option in select patients for end-stage cardiac pump failure, uncontrolled angina, or refractory ventricular tachycardia. With evolving surgical techniques and advances in immunosuppression since the first heart transplant in 1967, post-heart transplant survival has improved to approximately 90% at 1 year, with a median survival of greater than 12 years since 2000, with improvement in each era (Lund et al., J Heart Lung Transpl 35(10):1158–69, 2014, McKellar et al., N Engl J Med 377(23):2211–3, 2017, Bengel et al., Circulation 106(7):831–5, 2002, ISHLT. International Thoracic Organ Transplant (TTX) Registry Data Slides, 2023). The most common causes of early mortality following heart transplantation are graft failure and infection. In contrast, long-term morbidity stems from multi-organ failure, malignancy, and cardiac allograft vasculopathy (CAV) (Khush et al., Ann Cardiothoracic Surg 7(1):126–34, 2018). Globally and in the United States (U.S.), heart transplant volumes are increasing with >4600 heart transplants in the U.S. in 2023 (Administration HRS, National Data: US Department of Health &. Human Services, 2024). Mechanical circulatory support (MCS) device systems have been developed as a method of bridging patients to heart transplantation while waiting for a suitable donor. In this chapter, we review the indications, immunosuppression, and both short- and long-term complications of heart transplantation that are important for primary care providers.