Central nervous system (CNS) disease caused by Mycobacterium tuberculosis is an uncommon yet highly devastating manifestation of tuberculosis, which was universally fatal in the era before antituberculer therapy. CNS tuberculosis accounts for approximately 1% of all cases of tuberculosis, carries a high mortality and a distressing level of neurological morbidity, and disproportionately afflicts children and human immunodeficiency virus (HIV)-infected individuals. Due to its relative rarity and the protean nature of the symptoms, tuberculosis of the CNS remains a formidable diagnostic challenge. Because the burden of CNS tuberculosis lies largely in resource-starved regions of the world, additional challenges in implementing practical and usable methods to diagnose and treat this disease remain largely unmet. While other clinical manifestations of tuberculosis have received considerable research attention, fundamental questions regarding the pathogenesis, diagnosis, treatment, and management of CNS tuberculosis remain unanswered. What is the best way to diagnose CNS tuberculosis? What is the optimal treatment for this disease? How can we mitigate the significant neurological morbidity among survivors? How can we more rapidly diagnose CNS tuberculosis? These questions still remain open. The purpose of this review is to highlight the current understanding of the neuropathogenesis of M. tuberculosis and to discuss certain clinical, diagnostic, and therapeutic aspects of CNS tuberculosis.