The introduction of immunomodulatory treatments has transformed the management of patients with relapsing-remitting multiple sclerosis (MS), but has had no consistent benefit in progressive MS. Patients with primary or secondary progressive MS, therefore, are faced with relentless functional decline that remains without treatment. Clinical trials in progressive MS are clearly needed, but their design and conduct is challenging, and different from that of trials in relapsing-remitting MS. Challenges to reliable measurement of clinical progression, uncertainties about the natural history of progressive MS, and the unclear role of imaging outcomes all impede optimal trial design. Clinical trials in progressive MS have used time to a predefined change on the Expanded Disability Status Scale as their main outcome measure, which has had important consequences for trial duration and has led to inclusion of only a highly selected minority of patients. Here, we review the current approach to clinical trial design in progressive MS, outline key ongoing challenges, and suggest strategies to overcome such hurdles.