Primary angiitis of the central nervous system (PACNS), also known as primary central nervous system vasculitis, is a rare autoimmune condition characterized by exclusive involvement of the brain, spinal cord, and leptomeninges. With an estimated prevalence of 2.4 cases per million personyears in North America, PACNS represents one of the rarest vasculitides and continues to pose significant diagnostic and therapeutic challenges due to its heterogeneous clinical manifestations and lack of specific biomarkers. This critical review article provides a comprehensive overview of PACNS with emphasis on: (i) current understanding of pathophysiology and unique variations of clinical presentation, (ii) challenges and strategies in reaching a definitive diagnosis, and (iii) evaluation and comparison of pharmacological and neuromodulatory therapies currently available. Recent advances in understanding pathophysiology have identified elevated interleukin-17 in cerebrospinal fluid, distinct gene expression profiles including upregulation of TBC1D3C and TBC1D3L genes, and immune cell profiling showing increased intrathecal NK-cell and B-cell frequencies. Three histopathological subtypes have been characterized: granulomatous vasculitis (32-61%), lymphocytic vasculitis (24-79%), and necrotizing vasculitis (14-42%). Emerging biomarkers including neurofilament light chain, circulating endothelial cells, and soluble triggering receptor expressed on myeloid cells 2 (sTREM2) show promise for diagnosis and disease monitoring. Advanced neuroimaging modalities, particularly high-resolution vessel wall magnetic resonance imaging and positron emission tomography, demonstrate utility in detecting vessel wall inflammation and guiding biopsy site selection. Treatment approaches include glucocorticoids combined with cyclophosphamide for induction therapy, with mycophenolate mofetil, rituximab, azathioprine, and methotrexate used for maintenance. TNF- inhibitors have shown efficacy in refractory cases. Despite treatment, mortality ranges from 8-23%, and approximately 25% of patients experience severe disability. PACNS remains a diagnostically challenging condition requiring high clinical suspicion and comprehensive workup. Recent advances in understanding immunopathological mechanisms, identification of novel biomarkers, and development of advanced neuroimaging techniques offer promise for earlier diagnosis and more targeted therapeutic interventions. Brain biopsy remains the gold standard for diagnosis, though emerging non-invasive diagnostic modalities may reduce reliance on invasive procedures. Treatment strategies continue to evolve beyond traditional glucocorticoid and cyclophosphamide regimens, with biologics including rituximab and TNF-α inhibitors showing efficacy in refractory disease. Future multicenter collaborative studies are essential to validate emerging biomarkers, refine diagnostic criteria, establish evidence-based treatment protocols, and improve outcomes for this rare and heterogeneous disorder.