Cytomegalovirus continues to be one of the most clinically significant infections after solid organ transplantation. Classic definitions of patients at high risk for infection and tissue-invasive disease are focused on recipient-donor serostatus, type of organ transplanted, and overall level of immunosuppression. However, recent trends in clinical practice call for a reevaluation of cytomegalovirus infection risks after solid organ transplantation. Indeed, whereas early-onset cytomegalovirus infection is usually controlled by antiviral prophylaxis with ganciclovir and derivatives, delayed- and late-onset cytomegalovirus infection can develop after the completion of a course of preventive therapy. In addition, indirect effects of cytomegalovirus infection may occur as a result of persistent low-level viremia. Suboptimal dosing of antiviral drugs due to specific drug toxicities may result in the development of ganciclovir-resistant cytomegalovirus disease. The relationship between organ allograft rejection and cytomegalovirus infection and disease has been recognized for some time. Transplantation of increasing numbers of extended-criteria donor organs increases the risk of delayed graft function and acute rejection, prompting the use of more intensive immunosuppression. In addition, the trend to spare long-term exposure to calcineurin inhibitors has contributed to a resurgence in the use of polyclonal T-cell induction immunosuppressive agents, which may reduce host anticytomegalovirus immunity. We discuss the current trends in solid organ transplantation that provide a foundation for defining risks for cytomegalovirus infection and disease, including identification of patients who would benefit from more aggressive cytomegalovirus monitoring and prevention strategies.