Ganciclovir-resistant (GanR) cytomegalovirus (CMV) is an emerging clinical problem in organ transplant recipients, particularly recipients of kidney and pancreas and lung transplants. GanR CMV, a late posttransplantation complication, is observed predominantly among CMV-seronegative recipients of organs from seropositive donors, especially among recipients receiving intensive immunosuppression and having prolonged exposure to ganciclovir. Given the limitations of current diagnostic methods, if GanR CMV is clinically suspected, empirical treatment with intravenously administered foscarnet should be used in conjunction with reductions in immunosuppressive therapy and possibly CMV hyperimmune globulin. Better diagnostic tools and newer, less-toxic antiviral agents with different mechanisms of action are urgently needed to decrease the morbidity associated with this complication in organ transplant recipients.