Herpes simplex virus (HSV) and varicella zoster virus (VZV) are susceptible to acyclovir which inhibits viral replication through two viral enzymes, thymidine kinase (TK) and DNA polymerase. Resistance may occur, it is a rare phenomenon among immunocompetent patients but resistance is more frequent and may be associated with serious complications among immunocompromised patients. Virological survey of these at risk patients is needed to detect resistant virus as soon as possible through phenotypic tests performed on virus isolated on cell cultures. Resistant virus may also be genetically characterised by detection of mutations within TK and DNA polymerase genes. Pharmacological parameters also have to be taken into consideration and a determination of acyclovir blood concentration should be performed in case of unexplained therapeutic failure. Improvement of immune system, when possible, may resolve these infections. Alternative treatments using drugs such as foscarnet or cidofovir which have a different mechanism of action compared to acyclovir, are recommended but these molecules are often more toxic than acyclovir.