Cytomegalovirus (CMV) causes high morbidity and mortality in immunocompromised patients. The host immune response to CMV comprises specific and nonspecific cellular and humoral responses, but current knowledge supports a protective role only for cell-mediated immune responses. Although complete CMV eradication is unusual even in immunocompetent hosts, its morbidity can be limited by CMV-specific CD8+ cytotoxic lymphocytes supported by CD4+-mediated T lymphocyte helper activity. In patients with congenital or acquired deficiencies of cell-mediated immunity, recovery of CD4+ lymphocyte numbers and/or function coincides with cessation of CMV-associated morbidity. However, an immunological test that can predict protection against CMV disease across different types of high-risk patients is not yet available. In recent years, the introduction of antivirals active against CMV has improved the outcome of CMV disease. In addition, there is a continuous effort to develop CMV-specific immune-based therapies including vaccines and immune modulators such as cytokines, which may be of supplemental benefit in the control of CMV disease.