Viral-associated malignancies usually arise in the setting of altered immunity or with declines in immune function associated with aging. The main culprits are the lymphotropic herpesvirus, including Epstein-Barr virus (EBV) and human herpesvirus-8, which are the focus of this review. Chronic persistent infection and viral reactivation are the main risk factors for development of herpesvirus-associated malignancies and have provided the rationale for intensive monitoring of viral loads in some clinical contexts. Quantitative detection of EBV levels in the post-transplant period and following treatment of EBV-associated malignancies now have a proven role in outcome prediction. Both T-cell immunotherapy and humoral immunotherapies directed against latent viral antigens represent promising interventional approaches to treatment of viral-associated malignancies.