Despite intensive research over the past several decades, the etiology and pathogenesis of multiple sclerosis (MS) remain elusive. The last 20 years have seen only meager advances in the treatment of the disease in part because too much attention has been devoted to the process of demyelination and its relationship to the neurologic symptoms and recovery of the disease. A host of biological phenomena associated with the disease involving interactions among genetic, environmental, immunologic, and hormonal factors, cannot be explained on the basis of demyelination and, therefore, require refocusing attention on alternative explanations, one of which implicates the pineal gland as the pivotal mover of the disease. This review summarizes the evidence linking dysfunction of the pineal gland with the epidemiology, pathogenesis, clinical manifestations, and course of the disease. The pineal hypothesis of MS also provided the impetus for the development of a novel and highly effective therapeutic modality, one that involves the transcranial application of AC pulsed electromagnetic fields in the picotesla flux density.