Multiple sclerosis (MS) is a chronic inflammatory neurodegenerative autoimmune disease characterized by aberrant infiltration of immune cells into the central nervous system (CNS) and by the loss of myelin. Sclerotic lesions and various inhibitory factors hamper remyelination processes within the CNS. MS patients typically experience gradual cognitive and physical disabilities as the disease progresses. The etiology of MS is still unclear and emerging evidence suggests that microbiome composition could play a much more significant role in disease pathogenesis than was initially thought. Initially believed to be isolated to the gut microenvironment, we now know that the microbiome plays a much broader role in various tissues and is essential in the development of the immune system. Here, we present some of the unexpected roles that the microbiome plays in MS and discuss approaches for the development of next-generation treatment strategies.