It has been firmly established that IL-23 polarized T(H)17 cells are potent effectors in the pathogenesis of experimental autoimmune encephalitomyelitis (EAE). However, the relative importance of these cells in comparison to other encephalitogenic T(H) subsets, and the mechanisms that they employ to effect inflammatory demyelination, are topics of continuing investigation. Interestingly, deletion of individual 'T(H)17 cytokines', such as IL-17A, IL-17F, IL-22 and IL-21, does not phenocopy the complete EAE-resistance of IL-23-deficient mice. The instability of T(H)17 cells in vivo introduces an additional layer of complexity to their role in the context of relapsing or chronic disease. Recent data indicate that IL-23 drives the production of myeloid activating factors, such as GM-CSF, by myelin-reactive T cells and facilitates their accumulation in the CNS. This review discusses the above issues in relation to the use of T(H)17 cells and related factors as potential therapeutic targets and biomarkers in CNS autoimmune diseases such as multiple sclerosis (MS).