Recent studies have better defined the association between the human leukocyte antigen (HLA)-DR, cytotoxic T-lymphocyte antigen-4, interleukin-7 receptor, and interferon-gamma polymorphisms and susceptibility to multiple sclerosis (MS), while many more studies have been added to the controversial pool of likely false-positive and false-negative genetic association and linkage studies. Apolipoprotein E alleles may yet play an important role in disease course and cognitive impairment, although largely refuted as being directly associated with ambulatory measures of disease severity. Natural history studies have started to better define the clinical phenotypic heterogeneity of idiopathic inflammatory diseases of the central nervous system, fueling new hypotheses about immunopathogenesis of MS. Our understanding of phenotype measurement tools is improving. However, despite all the ongoing effort, the cause of MS and the determinants of heterogeneity in the clinical phenotype of MS remain largely unknown. As advances in our understanding of the immunobiology of MS start to bridge the gap between pathological and clinical natural history of the disease, biologically relevant phenotypes of MS will hopefully emerge to allow more specific treatment modalities to be developed and brought to practice.