Purpose of Review <p>Central nervous system (CNS) involvement in adult acute lymphoblastic leukemia (ALL) remains a critical determinant of treatment failure and long-term survival. This review provides a comprehensive, evidence-based framework for the diagnosis, risk stratification, prophylaxis, and treatment of CNS disease in adult ALL, with emphasis on the evolving challenges introduced by immunotherapy-based and chemotherapy-sparing regimens and presents our institutional approach to CNS-directed therapy.</p> Recent Findings <p>Modern CNS prophylaxis combining intrathecal chemotherapy with CNS-penetrating systemic agents has dramatically reduced CNS relapse rates, yet diagnostic and therapeutic limitations persist. The increasing use of immunotherapies, such as blinatumomab and inotuzumab ozogamicin, has improved systemic disease control, while CNS relapse is increasingly recognized in this context, particularly among heavily pretreated patients. This pattern likely reflects multiple factors, including limited CNS penetration, improved disease control that unmasks previously subclinical CNS involvement, and the high-risk biology of relapsed/refractory disease. In contrast, CD19-directed CAR T-cell therapies have demonstrated meaningful activity in CNS disease, while investigational strategies targeting leukemic trafficking pathways and IL-15 signaling offer additional preclinical promise.</p> Summary <p>As adult ALL treatment has shifted toward chemotherapy-sparing regimens, new concerns have emerged regarding disease control within the CNS compartment. Durable remission will require integration of rigorous intrathecal prophylaxis, risk-adapted systemic therapy, and novel agents capable of penetrating the CNS microenvironment into every treatment algorithm.</p>