The invention relates to methods for treating cytomegalovirus (CMV) in cells and tissues using targeted nucleases. The nucleases may be CRISPR/Cas9 complexes with guided RNA to target and inactivate CMV genomes within cells and tissues. The nucleases degrade or destroy the CMV genomes within the cells and tissues. Methods of the invention can be used to treat tissues, such as whole organs, prior to transplantation.