Purpose of reviewThis review summarizes the literature on acyclovir resistant herpes infections and the most recent data pertinent to diagnosis and treatment in the immunocompromised patient population. Recent findingsAlthough fairly rare, acyclovir resistant herpes infections can be challenging to diagnose. Clinicians should be aware of this entity when facing refractory herpes infections. With updated diagnostics, the diagnosis is usually made through viral culture and sequencing. Therapeutic choices depend on the extent of disease. Topical therapy may be appropriate for mucocutaneous disease. Intravenous antiviral therapies such as foscarnet and cidofovir may be necessary for disseminated, ophthalmologic, central nervous system, or visceral disease. Experimental therapies such as pritelivir are in clinical trials.