Disease caused by cytomegalovirus (CMV) infection can clinically manifest in a variety of ways in the immunodeficient host and lead to significant morbidity and mortality. Infections can be primary, occur as a result of reactivation of latent virus, or infection with a new strain of CMV. Cell-mediated immunity is the main defense against CMV disease. This component of the immune system is frequently affected in children who are born prematurely, have undergone solid organ transplantation or hematopoietic stem cell transplantation, or have infection with human immunodeficiency virus. Accordingly, these children are at increased risk for severe disease due to CMV. In addition, CMV itself alters cell-mediated immunity and may predispose hosts to other bacterial, fungal, or viral infections as well as predispose to graft rejection. The importance of CMV in these special populations of children, emphasizing epidemiology, risk factors, and preventive strategies, is reviewed.