Cytomegalovirus (CMV) is among the most important pathogens affecting the transplant recipient, with the spectrum of manifestations of CMV infection being quite broad. In the development of optimal strategies for the prevention and treatment of CMV infections, some of the most important information can be gained from patients who have failed either prophylaxis or therapy for CMV disease. Analysis of a cohort of these patients illustrates the role of primary infection in the immunologically naive patient for CMV, incompatibility of major histocompatibility complex (MHC) loci, and resistance to antimicrobial (antiviral) agents. Significant gaps in information include differentiating between viral strains, establishing the nature of viral latency, determination of host immunity to CMV, and optimal therapies for CMV infection. Elucidation of the factors that predispose to CMV infection will help to tailor and implement appropriate prophylactic strategies. New vaccines and orally bioavailable antiviral agents will play a significant role in the future care of transplant patients.