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The present review summarizes recent developments in pathogenesis, prevention, and management of ganciclovir-resistant cytomegalovirus infection.Basic science advances include reports of new resistance mutations and multidrug resistance. Innovative studies of the host immune response have shed light on differential risk. New laboratory techniques include rapid assays for resistance and measurement of ganciclovir levels.Clinical developments include studies on ganciclovir-resistant cytomegalovirus infection in thoracic transplant recipients and aspects of cytomegalovirus infection prevention. Although no resistance was seen in the valganciclovir arm of a prophylaxis trial, resistance has been described after both prophylactic and preemptive valganciclovir therapy. In the HIV realm, the incidence of ganciclovir-resistant cytomegalovirus infection has fallen dramatically. Newer options for therapy include maribavir, leflunomide, high-dose ganciclovir, switching to a sirolimus-based regimen, and the antimalarial drug, artesunate.Antiviral-resistant cytomegalovirus infection remains a feared complication of transplantation but is less frequently seen in AIDS patients in the current era. New research on resistance mutations and pathogenesis has enhanced clinical understanding of risk. Although preemptive strategies and valganciclovir prophylaxis are associated with less resistance than oral ganciclovir, resistant cytomegalovirus infection has not been eliminated. Several strategies and newer drugs hold promise for the future.