Axonal loss is well correlated with functional deficits in Multiple Sclerosis (MS); however, the molecular mechanisms that underlie this axonal loss are not understood. In this review we summarize evidence that antibodies to axolemma-enriched fractions (AEF) isolated from CNS myelinated axons may play a role in axonal destruction. AEF contains potent antigens that elicit high-titer antisera, which destroy neuritesin vitro, prevent neurite outgrowth, cause reactive changes in the neuronal cell bodies of origin and prevent myelination. We propose that these AEF antigens are cryptic because they are shielded from immune surveillance in vivo via the tightly sealed paranodal loops of myelin. Antibodies to AEF are found in cerebrospinal fluid (CSF) and sera of MS patients at higher levels compared with CSF or sera derived from patients with other neurological diseases. The potential identity of these cryptic antigens and their role in the axonal destruction characteristic of MS is discussed.