Progressive multiple sclerosis is characterised clinically by the gradual accrual of disability independent of relapses and can occur with disease onset (primary progressive) or can be preceded by a relapsing disease course (secondary progressive). An effective disease-modifying treatment for progressive multiple sclerosis has not yet been identified, and so far the results of clinical trials have generally been disappointing. Ongoing advances in the knowledge of pathogenesis, in the identification of novel targets for neuroprotection, and in improved outcome measures could lead to effective treatments for progressive multiple sclerosis. In this Series paper, we summarise the lessons learned from completed clinical trials and perspectives from trials in progress in progressive multiple sclerosis. We review promising clinical, imaging, and biological markers, along with novel designs, for clinical trials. The use of more refined outcomes and truly neuroprotective drugs, coupled with more efficient trial design, has the capacity to deliver a new era of therapeutic discovery in this challenging area.