Over the past 25 years, Osaka University has played a pivotal role in advancing heart and heart-lung transplantation in Japan, contributing to improved survival outcomes and treatment options for end-stage heart failure patients. By the end of December 2023, a total of 184 patients had undergone heart or heart-lung transplantation: 181 heart transplants and 3 heart-lung transplants. Despite these advances, severe donor shortages persist, resulting in extended wait times, with the mean duration for Status 1 patients now approaching 5 years. To address this, the institution has maximized the use of marginal donors and developed an extensive bridge-to-transplant strategy using left ventricular assist devices (LVADs). Immunosuppression protocols have also evolved, improving long-term outcomes, with our 5- and 10-year survival rates reaching 93.8% and 89.0%, respectively. This review discusses ongoing challenges and potential avenues for addressing donor scarcity, including innovations in organ allocation, xenotransplantation, and alternative therapies such as regenerative medicine. Our findings underscore Osaka University’s commitment to pioneering heart transplantation in Japan.