Immunohistochemistry (IHC) is a powerful experimental and diagnostic test useful for histomorphologic detection and localization of antigens, including rabies virus antigens. Optimization and interpretation of immunohistochemical assays are essential to provide accurate and reliable results, but pose significant challenges to scientists and technologists unfamiliar with the assay. Interpretation of IHC assays should always take place in the context of clinical, gross, and histopathological findings to insure correlation and eliminate false-positive results. This chapter briefly outlines the materials and methods, optimization, and interpretation of the test.