The human leukocyte antigen (HLA) gene cluster in chromosome 6p21.3 represents by far the strongest multiple sclerosis (MS) susceptibility locus genome-wide, explaining approximately 7%-10% of the total (genetic and non-genetic) variance. Two main biological issues contributed to thwart gene discovery efforts in MS. First, the effect attributable to each individual allelic variant is modest. Second, the true signals need to be isolated from the abundant genetic variation that characterizes the human population as a whole, leading to the inescapable conclusion that the discovery of genes influencing MS risk must rely primarily on very large patient datasets and well-matched controls. Concordance in families for some clinical metrics such as severity or age-of-onset suggests that genes modestly influence disease trajectory and course. High throughput methods of analysis have enabled the characterization of gene expression signatures characteristic of the disease and multiple efforts are underway to identify biomarkers of therapeutic response.