Managing patients after heart transplantation is challenging, since these patients have unique clinical complications (associated with the immunosuppressive therapy and cardiac allograft rejection) together with atypical clinical presentations for infection and systemic inflammatory response syndrome. Survival rates have improved substantially with the use of new immunosuppressive drugs. High vigilance, early diagnosis, and appropriate intervention for allograft-related and non–allograft-related syndromes with significant morbidity and mortality are the keys to long-term survival of patients after transplantation.