The human γ-herpesviruses Epstein-Barr virus (EBV or HHV4) and Kaposi sarcoma-associated herpesvirus (KSHV or HHV8) are each associated with around 2% of all tumors in humans worldwide. However, investigations into their infection, oncogenesis, and immune responses that protect from the associated tumors have been hampered by the exclusive tropism of these pathogens for humans. Mice with reconstituted human immune system components (HIS mice) provide the unique opportunity to study persistent infection, virus associated lymphoma formation, and cell-mediated immune control of EBV and KSHV. Moreover, since these pathogens are unique stimuli for cytotoxic human lymphocyte responses, they also allow us to characterize long-lasting cell-mediated immune control and the requirements for its initiation, which would also be desirable to achieve during antitumor vaccination in general. Thus, human γ-herpesvirus infection of HIS mice provides unique insights into the biology of these important human pathogens and human cell-mediated immune responses that are considered to be the main protective entity against tumors.