Despite major advances in therapy for multiple sclerosis (MS) patients, substantial unmet needs remain, particularly regarding the prevention of disability progression and the treatment of progressive and aggressive forms of the disease. While early use of high-efficacy therapies has improved inflammatory disease control, their impact on long-term neurodegeneration is limited, and therapeutic options for progressive MS remain scarce. Autologous hematopoietic stem cell transplantation (AHSCT) has emerged as a highly effective escalation strategy for selected patients with aggressive, inflammatory MS. Randomized trials and large observational cohorts demonstrate sustained suppression of inflammatory activity and high rates of no evidence of disease activity, with markedly improved safety profiles over time. Current consensus recommendations support AHSCT for highly active MS refractory to high-efficacy DMTs, while its use in non-inflammatory progressive MS remains debatable. Chimeric antigen receptor (CAR) T-cell therapies represent a novel approach targeting compartmentalized B-cell – driven pathology. Early clinical reports using CD19- and BCMA-directed CAR-T cells in progressive MS demonstrate CNS penetration, manageable toxicity, and preliminary signals of clinical improvement, warranting further investigation in controlled trials. Mesenchymal stromal cells (MSCs) offer immunomodulatory and neurotrophic properties with a favorable safety profile. Clinical studies suggest potential benefits, particularly with intrathecal administration, though efficacy remains inconsistent due to heterogeneous study designs, patient populations, and outcome measures. Overall, cell-based therapies hold promise for addressing unmet needs in MS, but robust randomized trials, optimized delivery strategies, and appropriate patient selection are essential to define their therapeutic role.