Although the aetiology of MS remains elusive, several genetic approaches have provided clues to the underlying molecular pathogensis. In addition to the well known association to HLA class II alleles, weak but highly significant association to the interleukin-7 receptor and interleukin-2 receptor genes has recently been established. A series of other promising candidate genes identified in large genome screens are under evaluation. The genetic predisposition to MS is so far shown to be mediated by common polymorphisms in genes encoding molecules involved in T cell activation and homeostasis, but only a small proportion of the potential susceptibility genes have yet been identified. Analyses of transcribed immune receptor genes have revealed evidence of antigen-driven clonal expansion of lymphocytes, and may also provide tools for charting their specificites. Recently, attempts to identify disease-associated genes through transcriptional profiling have revealed new candidate players in MS pathogenesis. Whereas genetic studies in humans may identifiy individual molecular players, transgenic animal models allow detailed examination of molecular pathways. These studies have shown that in addition to altered protein function, alteration of gene expression may contribute to disease development. We here review how different genetic approaches can be combined to elucidate the immunopathogenesis of MS.