In the present review, we summarize the potential diagnostic and prognostic significance of three CSF proteins in patients with CIS/early MS: (1) 14-3-3 protein, showing upregulation of distinct isoforms, which deserve further investigation to elucidate a possible prognostic significance; (2) tau protein, which is helpful in distinguishing demyelinating disorders from diseases characterized by prominent axonal loss; (3) cystatin C, a marker changing its CSF expression in accordance with disease stage and progression. This evidence concerns the gene CST3 and demyelinating disease.