Interleukin (IL)-23 is a heterodimeric cytokine composed of a distinct p19 subunit and a p40 subunit, which it shares with IL-12. The dermatology and rheumatology communities have long surmised that anti-IL-12/23p40 antibodies suppress autoinflammatory disease owing to their effect on IL-12. The aim of this review is to bring to light new data from murine and human studies demonstrating that in fact IL-23 and its resulting Th17 pathway mediate the inflammatory cascade that induces psoriatic plaque formation. Evidence derives from lesional immunohistochemical analyses, genetic studies, and research in other autoimmune diseases. Although current IL-12/23p40 inhibitors have shown good efficacy and safety, data regarding the functional role of IL-12 in immune defense suggest that preserving this cytokine would be beneficial. To date, evidence from mouse models and preliminary data in human beings show that specifically targeting IL-23p19 may be a safer but equally efficacious treatment option.