The need to improve diagnostic precision in multiple sclerosis (MS) is widely recognized. In recent years, several novel magnetic resonance imaging (MRI) biomarkers have been proposed to enhance diagnostic specificity and reduce misdiagnosis. Some of these imaging biomarkers are deemed highly specific for MS and are likely ready to enter the MS diagnostic work-up, while others are still in their exploratory phase. In addition, new synthetic MRI contrasts and artificial intelligence-based diagnostic algorithms are being tested to reduce the time burden related to imaging data acquisition and analysis. In this review, we summarize the most recent advancement in the field, focusing on the adoption of these novel MRI biomarkers-whether used alone or in combination-for the differential diagnosis of MS.