The earliest research literature addressing sub-clinical characteristics of Multiple Sclerosis was largely focused on humoral immune components, particularly antibodies in the cerebrospinal fluid of MS patients. However, two decades later, in the 1990's, T cells were established as a major component of the underlying mechanism(s) of MS pathogenesis, especially since EAE, the mouse model of MS, could be readily induced by immunization with myelin derived peptides or passive transfer of encephalogenic T cells. This data has contributed to the concept that the role of humoral immunity in MS pathogenesis may be negligible. However, more recent studies have provided important insights regarding the role of humoral immunity in MS pathogenesis. The goals of this review are to 1) summarize evidence for and against the hypothesis that humoral immunity plays a central role in the pathogenesis of MS, and 2) summarize studies in the EAE model that directly tested the role of humoral immunity in pathogenesis of the disease. With this information, we hope to convince the reader that great strides have been made towards defining a central role of humoral immunity in MS pathogenesis, but that there is a substantial amount of work to be done (especially in the EAE model) to ensure that the contribution of humoral immunity to MS pathogenesis is effectively addressed.