Osteopontin (OPN) was shown to be involved in inflammatory and degenerative processes of the nervous system. In multiple sclerosis, the role of OPN has been studied in the inflammatory phase, where it was shown that the protein levels increase during disease relapses. Moreover, it was shown that subjects who carry a genotype associated with decreased protein levels tend to display a benign course. Taken altogether, these findings suggest that OPN may play a detrimental role in multiple sclerosis, at least in the inflammatory phase. In common neurodegenerative diseases, such as Parkinson's and Alzheimer's disease, OPN seems to act as a double-edged sword triggering neuronal toxicity and death in some contexts and functioning as a neuroprotectant in others. The involvement of OPN in several biological pathways and networks calls for more extensive research in order to unravel its role in the different disease phases and its potential as a therapeutic target.