Multiple sclerosis (MS) is a complex disease involving interactions among multiple genetic loci with modest effects and environment. The human leukocyte antigen (HLA) gene cluster in chromosome 6p21.3 represents by far the strongest MS susceptibility locus genome-wide, with the primary signal arising from the HLA-DRB1gene in the class II segment of the locus. Large, multicenter DNA collections have prospered as the development of new laboratory and analytical approaches has matured at a remarkable pace, allowing the pursuit of comprehensive “agnostic” genome-wide association studies to identify and characterize the non-HLA genetic component of MS. This article summarizes the new knowledge gained from this experimental approach.