In individuals with multiple sclerosis, physical and cognitive disability progression are clinical and pathophysiological hallmarks of the disease. Despite shortcomings, particularly in capturing cognitive deficits, the Expanded Disability Status Scale is the assessment of disability progression most widely used in clinical trials. Here, we review treatment effects on disability that have been reported in large clinical trials of disease-modifying treatment, both among patients with relapsing-remitting disease and among those with progressive disease. However, direct comparisons are confounded to some degree by the lack of consistency in assessment of disability progression across trials. Confirmed disability progression (CDP) is a more robust measure when performed over a 6-month than a 3-month interval, and reduction in the risk of 6-month CDP in phase III trials provides good evidence for the beneficial effects on disability of several high-efficacy treatments for relapsing-remitting disease. It is also becoming increasingly clear that therapies effective in relapsing-remitting disease have little impact on the course of progressive disease. Given that the pathophysiological mechanisms, which lead to the long-term accrual of physical and cognitive deficits, are evident at the earliest stages of disease, it remains a matter of debate whether the most effective therapies are administered early enough to afford patients the best long-term outcomes.