Summary: Advances in cytokine biology have helped us understand the complex communication that takes place between antigen-presenting cells and cells of the adaptive immune system, such as T cells, which collectively mediate an appropriate immune response to a plethora of pathogens while maintaining tolerance to self-antigens. The interleukin-12 (IL-12) cytokine family remains one of the most important and includes IL-12, IL-23, IL-27, and the recently identified IL-35. All four are heterodimeric cytokines, composed of an α chain (p19, p28, or p35) and a β chain (p40 or Ebi3), and signal through unique pairings of five receptor chains (IL-12Rβ1, IL-12Rβ2, IL-23R, gp130, and WSX-1). Despite the interrelationship between the cytokines themselves and their receptors, their source, activity, and kinetics of expression are quite different. Studies using genetically deficient mice have greatly enhanced our understanding of the biology of these cytokines. However, interpretation of these data has been complicated by the recent realization that p40−/−, p35−/−, and Ebi3−/− mice all lack more than one cytokine (IL-12/IL-23, IL-12/IL-35, and IL-27/IL-35, respectively). In this review, we compare and contrast the biology of this expanded IL-12 family and re-evaluate data derived from the analysis of these dual cytokine-deficient mice. We also discuss how the opposing characteristics of the IL-12 family siblings may help to promote a balanced immune response.