Several lines of evidence indicate a genetic contribution to multiple sclerosis (MS) both in terms of predisposition to the disease and of immunological mechanisms which are known to play crucial roles in MS pathogenesis. The presence of high- and low-risk areas for MS in neighbouring regions supports the theory that MS predisposition is influenced by a complex interaction of genetic and environmental factors. Therefore, the use of genetically homogeneous and geographically isolated populations becomes an increasing requirement to reduce biasing biological variables. Sardinians fulfil these conditions well because of their different phylogeny from Europeans and the unique selective pressures which shaped their genome. Sardinians display amongst the highest MS prevalence rates world-wide and increasing MS incidence rates over time. Also, MS in Sardinia is linked to distinct human leucocyte antigen (HLA) alleles and associated to different patterns of cytokine production from lymphoid cells of different HLA subtypes. In this context, recent findings and future perspectives on the peculiarities of Sardinian MS concerning genetic, immunological and epidemiological aspects are presented. So far, our results indicate that variations at the level of territorial distribution and HLA-association are present which render MS heterogeneous even in this ethnically homogeneous population.