The etiology of Multiple Sclerosis (MS) is unknown, but is believed to involve three factors (Table 3.1). The first is genetic vulnerability. Associated risk/susceptibility genes, protection genes, and disease severity genes are being identified at an increasing pace. Linked genes are not universal, and vary somewhat based on patient racial, ethnic, and geographic background. The second factor involves as yet unidentified environmental exposures, which probably occur at critical timepoints rather early in life. Both vitamin D deficiency and Epstein–Barr virus (EBV) infection have been implicated as important for development of MS. The final factor is the host immune system, which damages the central nervous system (CNS). MS is clearly an immune-mediated disease. It appears to be heterogeneous, however, with different pathways leading to disease expression [1]. Studies focused on pathology and immunology allow important insights into MS pathogenesis and pathophysiology. This chapter will review what has been learned from neuropathology, and current concepts on major immunologic disease factors.