Although cytomegalovirus (CMV) can cause a wide spectrum of multi-system disorders in HIV-infected patients, retinal disease is by far the most common clinical manifestation and may lead to blindness if untreated. We discuss the rationale for systematic case detection for CMV retinitis (CMVR) within the HIV-affected population, focusing particularly on resource-limited settings. The gold standard for detection of CMVR is indirect ophthalmoscopy performed by a trained ophthalmologist. However this is generally not feasible in resource-constrained settings. Alternative methods include fundus photography or the use of laboratory techniques to detect CMV infection. Training and deployment of non-ophthalmic personnel to detect CMVR by ophthalmoscopy or with novel strategies may be a paradigm shift that needs to occur in order to provide effective systematic case detection for those at risk of CMVR in resource-constrained settings. Further research is needed to determine the diagnostic accuracy and operational feasibility of different strategies in resource-limited settings.