Multiple sclerosis (MS) clusters with the so-called complex genetic diseases, a group of common disorders characterized by modest disease risk heritability and multifaceted gene-environment interactions. The major histocompatibility complex (MHC) is the only genomic region consistently associated with MS, and susceptible MHC haplotypes have been identified. Although the MHC does not account for all genetic contribution to MS, the other genetic contributors have been elusive. Microarray gene-expression studies, which also have not identified a major MS locus, have, however, been promising in elucidating some of the possible pathways involved in the disease. Yet, microarray studies thus far have been unable to separate the genetic causes of MS from the expression consequences of MS. The use of new methodologies and technologies to refine the phenotype, such as brain spectroscopy, PET and functional magnetic resonance imaging combined with novel computational tools and a better understanding of the human genome architecture, may help resolve the genetic causes of MS.