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, the therapeutic approaches to the disease include modalities aiming at downregulation of the various immune elements that are involved in this immunologic cascade. Since the introduction of interferons in 1993, which were the first registered treatments for MS, huge steps have been made in the field of MS immunotherapy. More efficious and specific immunoactive drugs have been introduced and it appears that the increased specificity for MS of these new treatments is paralleled by greater efficacy. Unfortunately, this seemingly increased efficacy has been accompanied by more safety issues. The immunotherapeutic modalities can be divided into two main groups: those affecting the acute stages (relapses) of the disease and the long-term treatments that are aimed at preventing the appearance of relapses and the progression in disability. Immunomodulating treatments may also be classified according to the level of the ‘immune axis’ where they exert their main effect. Since, in MS, a neurodegenerative process runs in parallel and as a consequence of inflammation, early immune intervention is warranted to prevent progression of relapses of MS and the accumulation of disability. The use of neuroimaging (MRI) techniques that allow the detection of silent inflammatory activity of MS and neurodegeneration has provided an important tool for the substantiation of the clinical efficacy of treatments and the early diagnosis of MS. This review summarizes in detail the existing information on all the available immunotherapies for MS, old and new, classifies them according to their immunologic mechanisms of action and proposes a structured algorithm/therapeutic scheme for the management of the disease.