Prevention of cytomegalovirus (CMV) infection is an important part of clinical care provided to patients after solid organ transplantation. While the optimal preventive strategy has not been defined, most centers rely on universal prophylaxis or pre-emptive therapy. This article comments on recent studies designed to identify strategies that effectively reduce the incidence of late-onset CMV disease as the main problem associated with prophylaxis, and on recent data regarding the development of CMV-specific immunity depending on the CMV-preventive regimen used. Despite an apparent trend to prefer prophylaxis in clinical practice, this approach does not seem to be based on robust evidence.