Highlights • Pancreatic cancer (PC) has attracted a great deal of attention owing to the poor outcome, increasing prevalence in the last years and delay diagnosis. Known as a complex disease, it involves genetic mutations, changes in tumour microenvironment and inflammatory component dominated by interleukin-6 (IL-6) and its activated pathways, like Janus Kinase-Signal Transducer and Activator of Translation3 (JAK-STAT3), Mitogen Activated Protein Kinase(MAPK) and Androgen receptor(AR). The pro-inflammatory cytokine, plays a central role in oncogenesis, cancer progression, invasiveness, microenvironment changes, treatment resistance, prognosis and associated co morbidities like cachexia and depression. Fulfilling these roles IL-6 requires special attention to understand its complexity in PC development. • IL-6 is a pleiotropic cytokine with multiple physiological and pathological functions. Its approach in PC development, progression, invasiveness and metastasis is multimodal, by affecting the pancreatic tissue since the beginning, enhancing PanIN formation, by activating JAK2-STAT3, MAPK and other pathways which contribute to oncogenesis. Playing a central role in patient’s prognostic, treatment resistance and other co morbidities like depression and cachexia, IL-6 must be classified as a potential outcome survival marker and a treatment target.