A mechanism is proposed that may explain the factors that initiate a multiple sclerosis (MS) lesion. It is based upon the following two hypotheses: (i) there is a lower stimulus threshold for upregulating the mechanisms that result in leukocyte infiltration in individuals predisposed to developing MS; (ii) the MS lesion is initiated as a reduction in blood flow to a localized region of white matter. This reduction in blood flow leads to: (a) degenerative white matter changes affecting oligodendrocytes; (b) upregulation of chemokines in the endothelial cells and/or glial cells; and (c) upregulation of cell adhesion molecules on endothelial cells. Signals from the hypoxemic and hypoglycemic glial cells, likely involving myelin molecules and cytokines, result in an inflammatory immune response that results in rampant demyelination. Evidence supporting the proposed mechanism is presented, as well as suggestions on how to test the validity of the proposal.