Several non-neoplastic processes, including infection, inflammation, demyelination, vasculitis, autoimmune disease, and post-treatment changes (radiation therapy or chemoradiation) can result in a mass-like, space-occupying lesion on conventional computed tomography (CT) or magnetic resonance (MR) imaging of the brain. Additionally, non-neoplastic processes can produce imaging findings that mimic nontumoral neoplastic involvement of the central nervous system. Such instances pose a substantial diagnostic dilemma for interpreting radiologists, as well as clinicians tasked with determining the appropriate diagnostic tests and therapeutic strategies for these patients. Nuclear medicine studies, including single positron emission computed tomography (SPECT) and positron emission tomography (PET), as well as hybrid SPECT/CT, PET/CT, and PET/MRI may offer important diagnostic insights into these challenging cases, often helping to differentiate these mimics from true brain neoplasms. In this review, we detail common and uncommon brain tumor mimics in specific context of PET and SPECT imaging of the brain, including the multimodality imaging appearance of tumor mimics and the potential roles these modalities may play in providing diagnostic clarity.