Long-term resistance to many infections depends on the innate ability of the immune system to coordinate the development of antigen-specific adaptive responses. Deficiencies in these events can result in increased susceptibility to pathogens, whereas an inability to regulate an appropriate response can lead to devastating pathological conditions. For over a decade, interleukin (IL)-12 has been recognized as the canonical cytokine that links innate and adaptive immunity, and with the discovery of IL-23 and IL-27 as cytokines related to IL-12, there has been a concerted effort to understand the relationship between these factors. The results emerging from these studies have provided fundamental new insights into the developmental pathways that promote the differentiation and function of CD4(+) T helper cells and offer a dramatically altered perspective on the cause and prevention of autoimmune disease. In this review, we aim to highlight the discoveries that have led to our current understanding of the biology of IL-23 and IL-27 in the context of their role in resistance to infection, immune-mediated inflammation, and cancer.