Since the first successful human renal transplants were performed in the 1950s, cytomegalovirus (CMV) has remained as the major infectious pathogen that has affected allograft and patient survival. Cytomegalovirus disease in renal transplant recipients can have serious direct clinical effects (eg, fever and organ invasion syndromes) and indirect consequences on allograft survival, risk of other opportunistic infections, and patient mortality. All of these effects increase the cost of care. Before the antiviral drug ganciclovir was developed, reduction of immunosuppression and immunoglobulin infusions were the major treatment strategies for CMV disease. Currently, ganciclovir and its prodrug, valganciclovir, are the mainstays of CMV disease treatment, preemptive therapy, and antiviral prophylaxis. However, limitations to the current management for CMV infection in transplant recipients have stimulated interest in developing new treatment strategies and drugs. This article discusses the current concepts and challenges and reviews potential newer options in the management of CMV infection after renal transplantation.