Purpose of Review <p>Refractory post-transplant CMV, with or without genotypic resistance, remains a challenging issue. Antivirals traditionally used for refractory CMV include foscarnet and cidofovir, which have major toxicities and suboptimal efficacy. In 2021, maribavir became the first antiviral drug approved for treatment of refractory CMV with or without resistance defined by genetic mutations (resistant/refractory CMV or “R/R” CMV). However, much remains to be learned. This review presents an illustrative case and summarizes current literature on real-world outcomes of maribavir treatment, as well as other interventions for R/R CMV.</p> Recent Findings <p>Several post-marketing case series regarding real-world use of maribavir for R/R CMV have reported successful outcomes in 40–67%. An initial lower viral load may be predictive of likelihood of successful treatment. Exploring initial use of foscarnet to reduce a high viral load followed by maribavir, or use of combination therapy, is of interest. Resistance testing from the maribavir Phase 3 studies shows that maribavir resistance is often associated with nonresponse, that development of treatment-emergent resistance is more likely for maribavir than for valganciclovir, and a few maribavir resistance mutations also confer ganciclovir resistance. Letermovir is not recommended for treatment of active CMV, but letermovir prophylaxis may reduce the incidence of R/R CMV. Other candidate therapies for R/R CMV include CMV-specific T cells.</p> Summary <p>Patients with R/R CMV may benefit from maribavir in terms of virologic clearance and resolution of symptoms, with much less toxicity than other antivirals, but resistance will need to be carefully monitored. Optimal strategies such as initial use of foscarnet to reduce viral load, or combination antiviral therapy, need to be more rigorously studied. CMV-specific T cell therapy is promising but as yet not widely available.</p>