Therapeutic strategies for multiple sclerosis have radically changed in the past 15 years. Five regulatory-approved immunomodulatory agents are reasonably effective in the treatment of relapsing–remitting multiple sclerosis, and appear to delay the time to progression to disabling stages. Inhibiting disease progression remains the central challenge for the development of improved therapies. As understanding of the immunopathogenesis of multiple sclerosis has advanced, a number of novel potential therapeutics have been identified, and are discussed here. It has also become apparent that traditional views of multiple sclerosis simply as a CD4⁺ T-cell-mediated disease of the central nervous system are incomplete. The pathogenic role of other immune components such as the innate immune system, regulatory T cells, T helper 17 cells and B cells is reaching centre stage, opening up exciting avenues and novel potential targets to affect the natural course of multiple sclerosis.