After renal transplantation, immunosuppressive medications must be taken long-term to avoid acute rejection and the cascade of events leading to "chronic allograft dysfunction" and loss. In the past, when posttransplant immunosuppression was limited to azathioprine and prednisone, acute rejection episodes were common, and it was difficult to identify the impact of medication noncompliance. However, with more potent and effective drugs, acute rejection is uncommon, and medication noncompliance emerges as an increasingly important factor in the outcome of solid-organ transplantation. Recent studies have clearly demonstrated that medication noncompliance leads to an increased incidence of acute rejection, chronic rejection, and graft loss. Today, although a number of questions remain unanswered, new methodologies, such as electronic monitors, provide opportunities to study medication noncompliance and its risk factors, and the potential for earlier intervention to improve clinical outcomes.