Multiple sclerosis, which is the most common cause of chronic neurological disability in young adults, is an inflammatory, demyelinating and neurodegenerative disease of the central nervous system (CNS), which leads to the formation of multiple foci of demyelinated lesions in the white matter. The diagnostic is based currently in magnetic resonance image (MRI) and evidence of dissemination in time and space. However, this could be facilitated if biomarkers were available to rule out other disorders with similar symptoms as well as to avoid the cerebrospinal liquid (CSF) analyses, which requires an invasive collection. Additionally, the molecular mechanisms of the disease are not completely elucidated, especially those related to the neurodegenerative aspects of the disease. The identification of biomarkers candidates and molecular mechanisms of multiple sclerosis may be approached by proteomics. In the last 10 years, proteomic techniques have been applied in different biological samples (CNS tissue, CSF and blood) from multiple sclerosis patients and in its experimental model. In this review, we summarize these data, presenting their value to the current knowledge of the disease mechanisms, as well as their importance as identification of biomarkers or treatment targets. This article is protected by copyright. All rights reserved.