Despite advances in medical and electrical therapies for heart failure, morbidity and mortality remain high and patients often progress to end-stage heart failure. Over the last five decades, heart transplantation is considered a standard therapy for select patients with end-stage heart failure. However, while heart transplantation has become a treatment of choice for end-stage heart failure, challenges still exist for improvement in the short- and long-term outcomes. While there is an increase in the number of patients with end-stage heart failure, the number of donor organs remains a major limiting factor. Heart transplantation candidates in the current era are also more complex: older, antigen-sensitized, and on mechanical circulatory support at the time of listing and transplant. Such potential heart transplant recipients have an increased chance of problems, including antibody-mediated rejection and primary graft dysfunction. Recent advances could address the current challenges and include: 1) attempts to expand the pool of donor hearts; 2) changes in heart transplantation allocation policy allowing for more equitable organ distribution; and 3) advances in the management of antibody sensitization. Developments in these areas could result in improved survival and quality of life for heart transplantation recipients.