Multiple sclerosis (MS) is characterized by episodes of inflammatory damage to myelin and oligodendrocytes in the central nervous system mediated by T, B, and Natural killer lymphocytes of various types, antibody and complement, dendritic cells, macrophages, microglia, and secreted cytokines and chemokines. These relapses cause significant neurologic dysfunction, which is only partially reversible, and eventual secondary progressive neurologic decline frequently occurs. Interferon-beta (IFNβ) has been a mainstay of MS treatment for more than 20 years after being proven to reduce relapse frequency and development of new lesions on magnetic resonance imaging. However, patient response is highly variable and the exact mechanisms of action are not fully understood. Breakthrough relapses and secondary progressive neurologic decline remain significant concerns in long-term MS treatment. Biomarkers may help elucidate the beneficial effects of IFNβ in MS and possibly guide therapeutic decision making given the variety of different therapies now available with varying mechanisms of action and risks. Various serum and cerebrospinal fluid candidate biomarkers have been described, but none have yet been proven to carry sufficient predictive reliability for routine clinical use.