Herpesviruses are known for their persistent lifelong latent infection, which is made possible by their vast repertoire of immune-evasion strategies. We have previously shown that a human cytomegalovirus (HCMV) microRNA represses expression of the stress-induced Natural Killer (NK) cell ligand, MICB, to escape recognition and consequent elimination by NK cells. Here, we show functional conservation among diverse microRNAs derived from different herpesviruses, including HCMV, Kaposi's sarcoma-associated herpesvirus (KSHV), and Epstein-Barr virus (EBV), in their ability to directly target MICB mRNA and reduce its expression. Although the various viral microRNAs share no sequence homology, they are functionally similar and target MICB at different yet adjacent sites during authentic viral infection. The finding that different herpesvirus microRNAs target MICB indicates that MICB plays a pivotal role in the clash between herpesviruses and humans.