There is evidence that gender influences the clinical course of Multiple Sclerosis (MS). Symptom prevalence as well as characteristics differs between the sexes. These differences can be, at least partly, explained by gender differences in the characteristics of tissue damage and disease progression measured by Magnetic Resonance Imaging (MRI). The interaction between sex hormones and MS damage, supported by both MRI and clinical evidence, seems to play an important role in the clinical and sub-clinical gender bias in MS. Experimental data testing directly the effects of sex hormones on brain damage and their clinical relevance show that sex hormones have the potential of exerting anti-inflammatory and protective effects on brain tissue. Both data in experimental models and patient studies discussed in this review encourages a gender-based approach to MS.