In the immediate postoperative period, close attention must be paid to hemodynamic stability by focusing on preventing right ventricular failure and maintaining chronotropic competence. Preoperative support of the recipient circulation by mechanical assist devices appears to significantly increase the risk of post-transplantation primary graft failure. Primary cardiac allograft failure accounts for 40 percentage of mortality within 30 days of heart transplantation (HT). Following HT, the use of intraoperative and peri-operative corticosteroids remains the mainstay of early therapy. Monitoring of therapeutic drug levels is important but there is some controversy in how best to monitor the target levels of calcineurin inhibitors (CNIs). Early after transplantation, particularly in the first 3 months when the risk of rejection is highest, invasive biopsies are recommended at decreasing intervals. Close vigilance for re-emergence of circulating antibodies is needed, and newer approaches using complement inhibitors or intensive B-cell modulating drugs such as bortezomib are being studied.