Multiple sclerosis is an immune-mediated inflammatory disease of the central nervous system characterised by demyelination, neuroaxonal loss and a heterogeneous clinical course. Multiple sclerosis presents with different phenotypes, most commonly a relapsing-remitting course and, less frequently, a progressive accumulation of disability from disease onset (primary progressive multiple sclerosis). The majority of people with relapsing-remitting multiple sclerosis, after a variable time, switch to a stage characterised by gradual neurological worsening known as secondary progressive multiple sclerosis. We have a limited understanding of the mechanisms underlying multiple sclerosis, and it is believed that multiple genetic, environmental and endogenous factors are elements driving inflammation and ultimately neurodegeneration. Axonal loss and grey matter damage have been regarded as amongst the leading causes of irreversible neurological disability in the progressive stages. There are over a dozen disease-modifying therapies currently licenced for relapsing-remitting multiple sclerosis, but none of these has provided evidence of effectiveness in secondary progressive multiple sclerosis. Recently, there has been some early modest success with siponimod in secondary progressive multiple sclerosis and ocrelizumab in primary progressive multiple sclerosis. Finding treatments to delay or prevent the courses of secondary progressive multiple sclerosis is an unmet and essential goal of the research in multiple sclerosis. In this review, we discuss new findings regarding drugs with immunomodulatory, neuroprotective or regenerative properties and possible treatment strategies for secondary progressive multiple sclerosis. We examine the field broadly to include trials where participants have progressive or relapsing phenotypes. We summarise the most relevant results from newer investigations from phase II and III randomised controlled trials over the past decade, with particular attention to the last 5 years.