Cholangiocarcinoma (CCA) is a relatively rare, highly aggressive malignancy of the biliary network that arises in an intense inflammatory and desmoplastic hepatic environment. CCA risk factors vary but proinflammatory precursor conditions strongly predispose to the initiation and progression of bile ductular cancers. Molecular genetic profiling clarified the existence of various CCA pathological subtypes. In several independent studies, the chronic inflammatory CCA tumor type was associated with reduced overall survival and poor patient outcomes. Omics approaches identified a molecular signature of differentially expressed hub genes with prognostic implications. Several members of this gene set encode proteins that comprise the senescence-associated secretory phenotype (SASP) including SERPINE1, a serine protease inhibitor and a prominent SASP member that promotes aggressive behavior in a broad spectrum of malignancies. This review highlights the increasingly complex relationship between the inflammatory CCA microenvironment and the role of the SASP in bile ductular tumor progression.