Immune fitness is critical in the pathogenesis and outcome of cytomegalovirus (CMV) infection. CMV disease is seen almost exclusively among individuals with an immature or defective immune system, such as patients with AIDS, transplant recipients and the developing fetus. These observations have generated interest in immune-based strategies for the management of CMV disease. Among the immune-based therapies that have been investigated in experimental and clinical settings are: passive immunotherapy with immunoglobulin; CMV vaccination; adoptive CMV-specific T-cell immunotherapy; and immune reconstitution strategies (HAART in AIDS patients, and a reduction in pharmacologic immunosuppression among transplant recipients). However, except for immune reconstitution strategies, there is no widely accepted immune-based strategy that is proven to be highly effective for CMV disease management. The benefits of immunoglobulins remain debated in an era when antiviral therapy is widely available. CMV vaccination and adoptive immunotherapy, on the other hand, remain experimental, but have had encouraging preliminary results.