Traditionally, the brain has been considered an “immunologically privileged” organ. Under normal conditions, the blood‐brain barrier (BBB) is highly effective in preventing both cellular and humoral constituents of the blood from entering the brain parenchyma. In certain pathological conditions, such as viral infections and demyelinating disorders, the BBB may become altered, activated T cells and monocytes may gain access to the brain parenchyma, and microglia may assume the functions of antigen‐presenting cells and macrophages. Naturally‐occurring or clinically‐induced immunosuppression may dramatically alter various cellular and/or humoral aspects of the immune system. Consequently, the brain may become susceptible to disorders that would otherwise be excluded or may develop more severe manifestations of diseases, such as certain infections. This review considers the neuropathologic aspects of various conditions that may be encountered in the setting of both acquired and inherited immunosuppression. The major categories include infectious, neoplastic, vascular, and metabolic disorders. The review also briefly addresses the neuropathology of complications of chemo‐therapeutic agents, radiotherapy, and organ transplantation inasmuch as they often occur in the clinical setting of acquired immunosuppression.