IL-12 and IL-23 are closely related cytokines with important roles in the regulation of tissue inflammation. Converging evidence from studies in mice, human observational studies and population genetics supports the importance of these cytokines in the regulation of mucosal inflammation in the gut in particular. Ustekinumab, a therapeutic antibody targeting both cytokines is now widely licensed for the treatment of Crohn’s disease, including in Europe, the USA, Canada and Japan, whilst agents targeting IL-23 specifically are in late-phase clinical trials. We review the emerging understanding of the biology of IL-12 and IL-23, as well as that of their major downstream cytokines, including IL-17. In particular, we discuss how their biology has influenced the development of clinical trials and therapeutic strategies in IBD, as well as how findings from clinical trials, at times surprising, have in turn refocused our understanding of the underlying biology.