The heterodimeric cytokines IL-12 and IL-23 play a key role in T helper cell and innate lymphocyte cell differentiation and expansion. They are composed of a shared p40 chain, which pairs with a p35 or p19 chain to form IL-12 and IL-23, respectively. Preclinical model systems have predicted an important role of the p40 chain in intestinal inflammation. Moreover, genome-wide association studies have revealed that variants of the gene encoding the IL-23 receptor, as well as the locus harboring the gene encoding the p40 chain, confer genetic risk for developing Crohn's disease (CD) and ulcerative colitis (UC). Two monoclonal antibodies neutralizing the p40 chain (ustekinumab and briakinumab) and hence blocking both IL-12 and IL-23 activity, have been developed, which demonstrated clinical benefit in early phase trials, and hinted towards efficacy in a subpopulation of patients with CD who had failed prior anti-TNF antibody treatment. A dedicated phase 3 clinical trial of ustekinumab in patients suffering from moderate-to-severe CD who had previously failed anti-TNF antibody treatment indeed demonstrated a significant benefit over placebo for clinical response, but not remission, in this particularly difficult to treat patient population. Here we review the immunological and genetic background to anti-IL-12/IL-23-directed therapeutic strategies, and the lessons that can be learned from results of these and related clinical trials that tackle associated biological pathways.