As its historical name glioblastoma multiforme implies, glioblastoma is a histologically diverse, World Health Organization grade IV astrocytic neoplasm. In spite of its simple definition of presence of vascular proliferation and/or necrosis in a diffuse astrocytoma, the wide variety of cytohistomorphologic appearances overlap with many other neoplastic or non-neoplastic lesions. Here, after a brief review of glioblastoma is provided, the differential diagnostic possibilities with an emphasis on mimics and pitfalls are discussed. To provide an approach applicable to diagnostic practice, these discussions are grouped arbitrarily according to general malignant appearance such as pleomorphic xanthoastrocytoma and ganglioglioma, especially their anaplastic versions, and cellular features such as small cell and epithelioid glioblastoma. Some non-neoplastic lesions that can potentially be mistaken for glioblastoma under certain circumstances are also briefly mentioned. Additional studies, including immunohistochemistry and molecular markers, are included where applicable. Otherwise, exhaustive review of these individual entities, including their epidemiology and molecular biology, is outside the scope of this discussion.