A wealth of data confirms that genetic variation is an important determinant of multiple sclerosis (MS) risk. Population, family and molecular studies provide strong empirical support for a polygenic model of inheritance, driven primarily by allelic variants relatively common in the general population. The major histocompatibility complex (MHC) in chromosome 6p21.3 represents by far the strongest MS susceptibility locus genome-wide and was unambiguously identified in all studied populations. The primary signal arises from the HLA-DRB1 gene in the Class II segment of the locus, with hierarchical allelic and haplotypic effects. Independent protective signals in the telomeric Class I region of the locus have been described as well. Over the last 6 years, large multicenter DNA collections have thrived and the development of new laboratory and analytical approaches has matured at a remarkable pace, allowing pursuit of comprehensive 'agnostic' genome-wide association studies to identify and characterise the non-MHC genetic component of MS. Taken together, the results have provided unambiguous evidence for the association of over 100 non-MHC loci with disease susceptibility. Follow-up experiments refined some of the association signals (IL2RA and CD58), identified gene-gene interactions (HLA-DRB1/EVI5) and revealed mechanistic insights into the functional consequences of the identified gene variants, most notably an increase in the soluble to membrane-bound ratio for IL-7, IL-2 and TNF receptors and a tyrosine-protein kinase 2-mediated immune deviation. These results significantly broaden our understanding of disease pathogenesis and permit, for the first time, modeling an individual's disease risk within the context of his or her familial history. Progress in identifying additional risk alleles is likely to be rapid in the near future. Although the effect of any given predisposing variant is modest, the possibility exists that multifaceted gene-gene and/or gene-environment interactions could substantially increase the contribution of some variants to the overall genetic risk. In addition, susceptibility genes may be subject to epigenetic modifications, which greatly increase the complexity of MS inheritance. Despite these remarkable advances, the knowledge of MS genetics remains incomplete. For example, a key but unresolved question is whether genetic variants influence disease trajectory. Ongoing efforts to fully characterize the repertoire of genes that predispose to MS and modulate its presentation is discussed. Functional characterization of even a moderate genetic effect on MS pathogenesis by a known gene or group of genes can assist in elucidating fundamental mechanisms of disease expression and yield important therapeutic opportunities.