Two distinct processes contribute to the spectrum of human cytomegalovirus (HCMV)-induced pathology. In the first instance, cytopathic effects appear to occur as a direct result of virus replication. This type of disease is characterized by persistent HCMV infection of neural or gastrointestinal tissue, which results in HCMV retinitis, encephalitis, hepatitis, or gastroenteritis. Direct cytopathic effects of HCMV are associated with congenitally acquired or acquired immune deficiency syndrome-related manifestations of HCMV infection. A second type of HCMV-associated disease process is driven by immunopathologic mechanisms and results in variable mononucleosis-like syndromes and/or pneumonia in normal or partially immunosuppressed individuals. Human cytomegalovirus-associated interstitial pneumonia appears to derive from a combination of these two types of disease processes. Here, persistent viral infection, immunopathologic mechanisms, and virus-induced expression or repression of cellular genes each constitutes an important factor in pathogenesis. An understanding of the multiple underlying mechanisms of pathogenesis is crucial to devising optimum treatment approaches.