The pathogenesis of multiple sclerosis (MS) and neuromyelitis optica (NMO) results from complex interactions between multiple genetic and environmental factors, both of which can confer susceptibility or resistance to the diseases. To date, genome-wide association studies of European descendants have identified 110 variants associated with MS that are outside of the major histocompatibility complex region. It is noteworthy that most of these variants involve immunologically relevant genes. Nevertheless, the majority of heritability of MS and NMO remain to be discovered (missing heritability). The application of next-generation sequencing technology combined with recent advances in genome analysis will provide robust data sets for MS and NMO cohorts to enable a much more detailed understanding of these diseases.