Clinicians and pathologists have been inundated by published reports of new and potentially interesting diagnostic, prognostic, and putative predictive “markers” whose expression (or loss) holds great promise for more enlightened diagnoses and ultimately better patient care. Although an understanding of therapeutically (and possibly diagnostically) relevant pathways of glioblastoma may be at hand, significant challenges remain. Many immunohistochemical and genetic tests have proven to be useful in the stratification of clinical trials, whereas the utility of many others for the day-to-day practice of pathology awaits further study and validation. The importance of critical literature review and careful consideration of practical issues such as test standardization, compliance, cost-effectiveness, and availability must all be considered before implementing any new diagnostic test. This review will focus on the role of immunohistochemistry in the routine diagnosis of astrocytic and oligodendrocytic tumors and in assisting with the diagnosis of some less common gliomas that have ependymal-like features. It will conclude with a summary of molecular and genetic studies, which not only hold great promise for improved diagnosis, but also reveal prognostic information on disease outcome and predict response to treatment or provide biologic targets for novel therapies.