The focus of immunohistochemistry as applied to nervous system tumors is in identifying the neoplasm present and evaluating margins between normal and neoplastic tissue. Although not always utilized by specialists in neuropathology, immunohistochemistry remains useful to resolve concerns about the differentiation and rate of tumor growth. The aims of this review are to discuss the utility of immunohistochemical reagents currently used in diagnosis of canine and feline intracalvarial tumors, to indicate the applicability of some tests currently used in human nervous system tumors for domestic species, and to evaluate a few less commonly used reagents. A panel of biomarkers is usually needed to confirm a diagnosis, with groups of reagents for leptomeningeal, intraparenchymal, and ventricular neoplasms. In the future, signature genetic alterations found among feline and canine brain tumors-as correlated prospectively with diagnosis, rate of enlargement, or response to treatment-may result in new immunohistochemical reagents to simplify the task of diagnosis. Prospective studies determining the type and proportion of stem cell marker expression on patient longevity are likely to be fruitful and suggest new therapies. Due to increased frequency of biopsy or partial resection of tumors from the living patient, biomarkers are needed to serve as accurate prognostic indicators and assist in determining the efficacy of developing therapeutic options in nervous system tumors of dogs and cats.