The recent discoveries of the two interleukin (IL)-12-related cytokines, IL-23 and IL-27, reveal that the regulation of cellular immunity is more complex than originally thought. Until these discoveries, the role of IL-12 in modulating cellular immune responses had been overestimated due to the belief that the IL-12 p40 subunit was unique to IL-12. However, because p40 is shared between IL-12 and IL-23, it would be expected that p40(-/-) mice are doubly deficient in IL-12 and IL-23. Indeed, the essential role previously attributed to IL-12 in experimental autoimmune encephalitis during studies of p40(-/-) mice has been shown to be due to IL-23 instead. The newest addition to the IL-12 cytokine family, IL-27, has unique features as well. Its specific action on naive CD4+ T cells in both mice and humans appears to distinguish it from the other IL-12 family members. Although related, the IL-12 family of cytokines and their receptors have distinct patterns of expression and unique effects on developing immune responses. This review summarises much of the pertinent literature on the IL-12 cytokine family and provides predictions regarding their potential therapeutic roles based on what has been learned about their functions in vitro and in vivo in gene-deficient mice.