Recent studies demonstrated an IL-17-producer CD4+ T cell subpopulation, termed Th17, distinct from Th1 and Th2. It represents a different pro-inflammatory Th-cell lineage. This notion is supported by gene-targeted mice studies. Mice lacking IL-23 (p19-/-) do not develop experimental autoimmune encephalomyelitis (EAE) or collagen-induced arthritis (CIA), while knockout mice for the Th1 cytokine IL-12 (p35-/-) strongly develop both autoimmune diseases. Disease resistance by IL-23 knockout mice correlates well with the absence of IL-17-producing CD4(+) T lymphocytes in target organs despite normal presence of antigen-specific-IFN-gamma-producing Th1 cells. This finding may thus explain previous contradictory reports showing that anti-IFN-gamma-treated mice, IFN-gamma- or IFNR-deficient mice develop CIA or EAE. TGF-beta, IL-6 and IL-1 are the differentiation factors of Th17 cells. IL-23 is dispensable for this function, but necessary for Th17 expansion and survival. The master regulator that directs the differentiation program of Th17 cells is the orphan nuclear receptor RORgammat. IL-27, a member of the IL-12/IL-23 family, potently inhibits Th17 development. Evidence suggesting rheumatoid arthritis and multiple sclerosis as primarily IL-17 autoimmune inflammatory-mediated diseases is rapidly accumulating. The IL-17/23 axis of inflammation and related molecules may rise as therapeutic targets for treating these and perhaps other autoimmune diseases.