Transfusion-transmitted cytomegalovirus (CMV) infection (TT-CMV) continues to complicate blood transfusion therapy, which can lead to severe morbidity or mortality in immunocompromised or immuno-immature recipients. The biological mechanisms that underlie TT-CMV (eg, viral latency in donor monocytes or stimulatory signals in the transfusion recipient leading to cytomegalovirus reactivation) are difficult to study in humans, but can be addressed in animal models. In this review, we discuss a mouse blood transfusion model, which can be used to investigate these issues as well as to validate methods to prevent TT-CMV in at-risk patients.