Multiple Sclerosis (MS) is a heterogeneous disease of unknown etiology. The current hypothesis proposes a complex interplay between an environmental agent and the immune system that induces an abnormal response in genetically predisposed persons, leading to the autoimmune disease of MS. In recent decades the incidence and prevalence of MS seem to have increased, which may be better explained by environmental rather than genetic changes. Some infectious agents have been implicated as the possible culprits, as they could be involved in the appearance of autoreactive T cells against myelin using different mechanisms. Among microorganisms, certain bacteria, such as Chlamydia (Chlamydophila) pneumoniae have been suggested, but viruses have generally been associated with MS etiopathogenesis, with human herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV) being the best studied in recent years. Updating a previous review, we reanalyze the role of these microorganisms in MS etiology in detail and discuss the contributions of the hygiene hypothesis and environmental agents, both infectious and non-infectious, in the explanation of epidemiological changes in MS.