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Multiple sclerosis (MS) witnessed relevant therapeutic progress in the last decade. This notwithstanding, safety, quality of life, and overtreatment remain elements of strong concern for patients. Safe and manageable therapies that can be used upon the (biological) onset of the disease, without risk of overtreatment, are important unmet needs in MS. Bacille Calmette-Guerin (BCG) vaccine may have these characteristics because it has beneficial results in early MS and its first demyelinating episodes. Safe, cheap, and handy, BCG vaccine seems appropriate as a frontline immunomodulatory approach for people with radiologically isolated syndromes (RIS; that is, a magnetic resonance imaging of the brain compatible with MS, without any symptom or sign of disease). A trial underway in RIS patients will contribute to verification of this hypothesis. Another promising field for adjuvant approach seems to be that of common disorders, such as Alzheimer’s and Parkinson’s disease, classically considered of neurodegenerative nature. Recent evidence consistently showed that neuroinflammation is a significant component underlying these neurological diseases, and BCG vaccine fosters immunoregulatory circuit and tissue repair in experimental models.