It is widely accepted that the main common pathogenetic pathway in multiple sclerosis (MS) involves an immune-mediated cascade initiated in the peripheral immune system and targeting CNS myelin. Logically, therefore, therapeutic approaches to the disease include modalities aiming at downregulation of the various immune elements that are involved in this immunological cascade. Since the introduction of interferons in 1993, more specific immunoactive drugs have been introduced, but still most of them can, at best, effectively modulate only the early relapsing phases of MS. The more progressed phases of the disease are not efficiently amendable by the existing immunomodulatory drugs. Moreover, localized and compartmentized inflammation in the CNS, which seems to be mostly responsible for the chronic axonal damage and resulting progression of disability, is less affected by the current drugs. A more radical approach to suppress all the inflammation in MS, including that into the CNS, could theoretically be achieved with high-dose immunosuppression using strong cytotoxic medications and resetting of the immune system by hematopoietic stem cell transplantation (HSCT). HSCT, both allogeneic and autologous, has been tried as a novel therapeutic approach in various autoimmune diseases. During the last 15 years several (mostly open) clinical studies evaluated the effect of HSTC on MS patients; the published papers showed that a high proportion of the HSCT-treated MS patients were stabilized, or even improved after the transplantation and have generally indicated a beneficial effect on disease progression. In this review, the rationale of HSCT and the summary of the results of the existing clinical trials are presented. Despite the fact that it is difficult to collectively summarize the results of all the trials, due to lack of uniformity in the conditioning and treatment protocols and of completed controlled studies, these clinical studies have provided a strong 'proof of concept' for HSCT in MS and have significantly contributed to our understanding of the advantages and disadvantages of each approach and HSCT protocol.