A major challenge in the routine practice of surgical neuropathology is the distinction between reactive astrocytosis, which may be because of non-neoplastic and neoplastic conditions, and a low-grade infiltrating diffuse astrocytoma [World Health Organization (WHO) grade II]. This can be particularly challenging with small biopsies that often yield limited amounts of tissue for pathologic study, especially considering the marked differences in prognosis and therapy after a pathologic diagnosis. This paper will review some basic principles of gliosis as an astrocytic reaction to a wide range of central nervous system insults and focus on some common diagnostic pitfalls such as (1) gliosis associated with brain tumor mimics, including demyelinating disease and infections, (2) gliosis associated with nonglial tumors such as craniopharyngioma, hemangioblastoma, metastases, and central nervous system lymphoma. New diagnostic methods have facilitated the differentiation between reactive astrocytosis and the diffuse gliomas. Of these, the use of mutated isocitrate dehydrogenase-1 (IDH-1) as a marker of diffuse infiltrating astroctomas, oligodendrogliomas, and a subset of glioblastomas (secondary glioblastomas) is particularly exciting for tissue diagnosis and patient prognosis. In addition IDH-1 may be useful to distinguish a diffuse infiltrating glioma from low-grade “focal” neoplasms such as the pilocytic astocytoma in histologically ambiguous cases. The discovery of BRAF mutations as molecular signatures of some pilocytic astrocytomas, gangliogliomas, and pleomorphic xanthoastrocytomas has provided another diagnostic tool for the pathologist. Only after a definitive diagnosis of a diffuse infiltrating glioma or a focal glioma is made should a tumor grade be applied and some practical issues in current glioma grading are provided.