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The modest activity of ACV against CMV prompted the development of another nucleoside analogue, ganciclovir, for the management of systemic and organ\u2010specific CMV diseases. Second\u2010line agents such as the pyrophosphate analogue foscarnet and the nucleotide analogue cidofovir have been approved subsequently. In contrast to ACV and ganciclovir, the latter drugs do not require selective phosphorylation by viral protein kinases to be converted into their active forms. Since the introduction of these antivirals, the emergence of drug\u2010resistant mutants has been constantly reported particularly in severely immunocompromised patients such as bone marrow and solid organ transplant recipients as well as HIV\u2010infected individuals. In this manuscript, we discuss the characteristics of the antiviral agents currently approved for the management of HSV, VZV and CMV diseases. In recent years, the resistance of CMV to antiviral drugs has been extensively reviewed. The emergence of antiviral drug resistance is also observed with other members of the <jats:italic>Herpesviridae<\/jats:italic> family, namely HSV\u20101, HSV\u20102, VZV and HHV\u20106, which are the focus of this review. More specifically, we describe the laboratory methods for assessing drug susceptibilities, the frequency and clinical significance of drug\u2010resistant infections and their management. 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