Primary vasculitis of the central nervous system (PCNSV) is a rare and diagnostically challenging form of vasculitis limited to the brain and/or spinal cord. It is a complex and often severe disease with multifaceted clinical and pathological appearances, suggesting multiple disease subtypes and the potential existence of multiple etiologic pathways. We describe in detail the clinical, imaging, and neuropathological findings of PCNSV summarizing literature data and our observations from a cohort of 131 patients diagnosed at Mayo Clinic over a 25-year period (1983-2007). Unlike systemic vasculitis, little is known regarding PCNSV pathogenesis and the involved immunological mechanisms. Increased recognition of the disease spectrum and in-depth characterization of its histopathologic and immunological phenotype will be critical to eventually understanding the underlying derangements and mechanisms driving PCNSV. Improved understanding of the pathogenetic mechanisms of the disease may also help determine whether the different histologic patterns and clinical subsets represent more than one disease and ultimately may permit development of novel diagnostic and therapeutic strategies for it.