Alloimmunity describes the recipient’s immune response to a transplanted organ from a genetically non-identical member of the same species. The primary targets for the alloimmune response are the major histocompatability complex (MHC) molecules located on the surface of nucleated cells in the allograft. Both cellular and antibody-mediated processes will result in rejection of the allograft is left unmodulated by immunosuppressive drugs. The routine use of induction therapy to provide early, intensive immunosuppression immediately after transplantation is currently practiced by fewer than 50% of heart transplant programs world-wide but may be of benefit in the subset of patients with the highest risk of acute rejection and in patients with impaired renal function to allow delayed initiation of calcineurin-inhibitors post-transplantation, since these agents can cause significant nephrotoxicity. Most modern immunosuppressive regimens consist of two or three drugs, including a calcineurin-inhibitor (either cyclosporine or tacrolimus), an antimetabolite agent (either mycophenolate mofetil or mycophenolate sodium), and tapering doses of corticosteroids over the first year. The proliferation signal inhibitors (sirolimus and everolimus) can be used in combination with either a calcineurin-inhibitor or an antimetabolite agent in patients with cardiac allograft vasculopathy or renal insufficiency. Due to their inhibitory effects on smooth muscle proliferation and absence of intrinsic nephrotoxicity, the proliferation signal inhibitors have been useful in both settings. However, the high incidence of drug-related adverse effects, including lower extremity edema and inhibition of wound healing, may limit their generalized use. The calcineurin inhibitors and proliferation signal inhibitors are heavily metabolized by the cytochrome P450 3 A4 pathway and therefore are susceptible to numerous drug interactions. Clinicians managing heart transplant patients should become familiar with the common agents that can increase immunosuppressive drug levels (calcium channel blockers, antifungal drugs, amiodarone, and grapefruit juice), decrease drug levels (rifampin, phenytoin, St. John’s wort), or potentiate the nephrotoxic properties of immunosuppressive agents (non-steroidal anti-inflammatory agents, aminoglycoside antibiotics). When these drugs are added to or deleted from a patient’s baseline regimen, immunosuppressive drug levels and renal function should be carefully monitored.