Antiviral agents are commonly used for cytomegalovirus (CMV) prophylaxis or therapy after solid organ transplantation. Until recently, the detection of drug-resistant CMV in this setting was rare, but ganciclovir resistance has now been reported to occur in 5-10% of high-risk patient subsets, such as those undergoing primary CMV infection. Persistent viral shedding or progressive CMV disease after several weeks of antiviral therapy may indicate a problem with drug resistance, though laboratory testing is required to confirm this. Rapid genotypic assays for specific mutations in the viral UL97 phosphotransferase or UL54 DNA polymerase genes can be used to detect resistance and predict cross-resistance to other drugs. The emergence of drug resistance may be reduced by optimization of host immunity, use of potent antiviral drug regimens, and adherence to dosing regimens that adequately suppress viral replication.