Secondary progressive multiple sclerosis (SPMS) is defined by the slowly progressive deterioration of clinical symptoms independent of relapse, following the early relapsing-remitting disease course. Diagnosis of SPMS is challenging and usually retrospective because of the lack of reliable diagnostic tests. There is also a lack of reliable clinical symptoms other than gait disturbance, which are well evaluated in the clinical setting. The pathogenic mechanisms driving SPMS are poorly understood, and therapy for SPMS remains limited. It is assumed that the characteristic features of neurodegeneration observed in SPMS are caused by chronic inflammation with compartmentalized T and B cells from the periphery, glial and mitochondrial dysfunction, and other factors. Neuroprotective agents, promotion of remyelination, and immunological modifications may be key targets for novel treatment strategies.