Central Nervous System (CNS) infections are associated with significant mortality and morbidity. Accurate diagnosis is necessary for prompt treatment and increased chances of survival. However, there are many challenges to correct diagnoses in resource-limited settings, including the HIV epidemic, late presentation of symptomatic individuals, limited availability of laboratory diagnostic tests as well as treatment, and inadequate access to funds accompanied by lack of financial support from developed countries. This article presents case reports of patients admitted to the Mulago Hospital in Kampala, Uganda that exemplify challenging diagnoses of tuberculous meningitis (TBM), cryptococcal meningitis (CM), toxoplasmosis, and primary CNS lymphoma (PCNSL). Also included is a literature review of the pathology, diagnosis, and treatment of TBM, CM, toxoplasmosis, and PCNSL in immunocompromised patients.