Interleukin (IL)-23, a member of the IL-12 cytokine family, plays a central role in immune-mediated inflammatory diseases (IMIDs) such as psoriasis, psoriatic arthritis, and inflammatory bowel disease (IBD). This review discusses the biology of IL-23, its signaling in IMIDs, and the effectiveness of IL-23 inhibition in treating these diseases. The authors propose studies to advance IL-23 biology and understand differences in response to anti-IL-23 therapy. Experimental evidence from these investigations could establish a novel molecular ontology centered around IL-23-driven diseases, improve current approaches to treating IMIDs with IL-23 inhibition, and ultimately facilitate the identification of optimal patients for anti-IL-23 therapy. IL-23 is produced by tissue-resident myeloid cells and promotes the expansion and survival of T helper (Th)17 cells, which produce proinflammatory cytokines like IL-17A and IL-22. IL-23 also stimulates other immune cells, including innate immune cells, and suppresses regulatory T (Treg) cell differentiation. In IMIDs, IL-23 is a key driver of inflammation, and targeting IL-23 can restore immune homeostasis and improve clinical outcomes. However, some patients show only partial responses, and the therapeutic benefit of IL-23 inhibition beyond the immediate cluster of IMIDs is unclear. The authors propose a multiomics approach to advance IL-23 science, including comprehensive studies to identify the spectrum of IL-23 receptor-expressing cells and provide insights into the role of IL-23 in driving IMIDs. They also discuss gaps in the understanding of IL-23 signaling and cellular activity, durability of treatment response, and future prospects for anti-IL-23 therapeutic intervention, including potential approaches for combination therapy.Interleukin (IL)-23, a member of the IL-12 cytokine family, plays a central role in immune-mediated inflammatory diseases (IMIDs) such as psoriasis, psoriatic arthritis, and inflammatory bowel disease (IBD). This review discusses the biology of IL-23, its signaling in IMIDs, and the effectiveness of IL-23 inhibition in treating these diseases. The authors propose studies to advance IL-23 biology and understand differences in response to anti-IL-23 therapy. Experimental evidence from these investigations could establish a novel molecular ontology centered around IL-23-driven diseases, improve current approaches to treating IMIDs with IL-23 inhibition, and ultimately facilitate the identification of optimal patients for anti-IL-23 therapy. IL-23 is produced by tissue-resident myeloid cells and promotes the expansion and survival of T helper (Th)17 cells, which produce proinflammatory cytokines like IL-17A and IL-22. IL-23 also stimulates other immune cells, including innate immune cells, and suppresses regulatory T (Treg) cell differentiation. In IMIDs, IL-23 is a key driver of inflammation, and targeting IL-23 can restore immune homeostasis and improve clinical outcomes. However, some patients show only partial responses, and the therapeutic benefit of IL-23 inhibition beyond the immediate cluster of IMIDs is unclear. The authors propose a multiomics approach to advance IL-23 science, including comprehensive studies to identify the spectrum of IL-23 receptor-expressing cells and provide insights into the role of IL-23 in driving IMIDs. They also discuss gaps in the understanding of IL-23 signaling and cellular activity, durability of treatment response, and future prospects for anti-IL-23 therapeutic intervention, including potential approaches for combination therapy.