Allograft dysfunction remains a major problem for long-term graft survival after kidney and heart transplantation. Current immunosuppressive regimens do not completely address the causes of allograft dysfunction which include acute rejection episodes, complications of immunodeficiency (for example, cytomegalovirus infection), nephrotoxicity from calcineurin inhibitors (cyclosporine and tacrolimus) and vascular remodeling and vasculopathy. Everolimus is a potent immunosuppressor that inhibits growth factor-stimulated proliferation of hematopoietic and nonhematopoietic cells, including vascular smooth muscle. Everolimus is indicated for the prophylaxis of acute rejection in kidney and heart transplant patients in a combined regimen with cyclosporine microemulsion and corticosteroids. Everolimus is formulated as both a tablet and a tablet for oral solution. It is rapidly absorbed and displays dose-proportional, stable pharmacokinetics. Everolimus has equivalent efficacy to mycophenolate mofetil in reducing the incidence of acute rejection after renal transplantation and superior efficacy to azathioprine after heart transplantation. Combination of everolimus with cyclosporine allows dose-reduction of cyclosporine while maintaining efficacy due to the synergistic immunosuppressive effects of the combination. Everolimus reduces intimal thickening of blood vessels to the graft and the incidence of allograft vasculopathy in heart transplantation. In both kidney and heart transplantation, the incidence of cytomegalovirus infection was lower in everolimus-treated patients compared with patients receiving the control treatment. Everolimus-related adverse events include elevated cholesterol and triglycerides, which respond to treatment, and decreased platelet count, which is transient. Nephrotoxicity may result from the combination of everolimus with full-dose cyclosporine but is mitigated by reducing the dose of cyclosporine. Everolimus is initiated at 0.75 mg b.i.d. with dose adjustments guided by therapeutic drug monitoring of predose blood levels. In clinical development trials, everolimus has demonstrated the ability to reduce the incidence of acute rejection episodes, cytomegalovirus infection and cardiac vasculopathy, thus addressing the primary causes of allograft dysfunction.