The World Health Organization recently updated its classification of central nervous system tumors, adding 8 entities, as well as defining new variants and morphologic patterns of existing entities. Despite the continued refinement of brain tumor histologic classification and grading, there remain some diagnostic "gray zones" that challenge general surgical pathologists and neuropathologists alike. These include the presence of oligodendroglial features in (mixed) oligoastrocytomas and glioblastomas (GBMs), GBM variants (such as small cell GBM), meningioma classification and grading, medulloblastoma variants, ependymoma grading, the presence of "neuronal features" in otherwise morphologically classic gliomas, and low-grade gliomas with high Ki-67 labeling indices. In the current review, we discuss these issues and offer some practical guidelines for dealing with problematic cases. © 2008 Lippincott Williams & Wilkins, Inc.