The clinical heterogeneity associated with progression to disability remains one of the mysteries surrounding multiple sclerosis (MS) and can be a source of consternation to patients and physicians alike. Patients who appear neurologically comparable at diagnosis often have widely divergent disease courses: some progress rapidly and require assistance to ambulate within a few years; others experience few relapses and remain almost neurologically intact for decades. Many have hypothesized that the phenotypic variability of MS stems from underlying genetic differences between patients.