Immunosuppressive therapy in clinical transplantation has evolved from general nonspecific suppression of the immune system to selective blockade of intracellular immune events, maximizing graft tolerance while minimizing toxicity. Cyclosporine 2-hour postdose level monitoring has been recommended as the single most sensitive sampling point for assessment of the area under the curve, and predictor of clinical outcomes in heart transplantation. Strategies for monitoring immunosuppressive drugs to improve efficacy without increased toxicity are critical as we move into the 21st century. Everolimus, a derivative of rapamycin, is a macrocyclic immunosuppressive agent with antiproliferative activity that is efficacious in preventing graft vasculopathy. Agents that increase the armamentarium against rejection allowing individualized therapy tailored to minimize complications, and prevent graft vasculopathy will improve our flexibility and may translate into improved long-term outcomes.