We contend that pro‐inflammatory effects in humans and in experimental models relate in part to underlying disease pathology (e.g. psoriasis), timing of an exogenous administration of IL‐22 (e.g. where infection is still active) and dose (pharmacological doses of IL‐22 conceivably activate not only STAT3 but also some classical inflammatory pathways) (Figure 1). The gene discussed is STAT3; the disease is psoriasis.