The development of a progressive course is by far the most deleterious event in the case of a multiple sclerosis (MS) patient. It occurs in about 90% of relapsing remitting patients by 20-25 years from onset. The clinical transition to secondary progressive MS is phenotypically distinctive and both patients and physicians acknowledge that a fundamental shift in the degree of responsiveness to anti-inflammatory therapies has occurred. This review discusses the clinical studies that provided important findings relating to our understanding on different mechanisms that may contribute to irreversible disability in MS.