Our understanding of virus control by natural killer (NK) cells relies mainly on in vitro observations. The significance of these findings for virus control in vivo is not yet fully understood. Complexity is added by the fact that many viruses, particularly herpesviruses, are equipped with sets of genes that, dependent on the genetic background of the host, modify the NK cell response. The advent of recombinant DNA technology and mutagenesis procedures for BAC-cloned viral genomes has made it possible not only to screen for viral proteins with such functions but also to assess their biological relevance. Mutant viruses with gene defects reveal the efficacy and complexity of NK cell control. Here, we describe procedures to assess the NK cell response to mouse cytomegalovirus (MCMV), a prominent virus model for studying NK cell functions in vivo.