Patients with HIV are living longer now than in the past, and with a better quality of life. During the advanced stages of HIV infection patients are at risk of cytomegalovirus (CMV) reactivation and subsequently CMV disease. It is important to review the evidence on whether CMV reactivation leads to CMV disease and what the best methods are for detecting such a reactivation. CMV polymerase chain reaction (PCR) can be used qualitatively to predict CMV disease and quantitatively to predict a general increase in mortality. CMV PCR can also be used to direct either prophylaxis or pre-emptive therapy to those most at risk of CMV disease. CMV PCR should be an integral part of the decision-making process when treating both new patients with CMV retinitis and those with disease reactivation.