Intrahepatic cholangiocarcinoma is typically characterized by a dense desmoplastic stroma, of which cancer-associated myofibroblasts (which express α-smooth muscle actin), are a major cellular component. These stromal myofibroblasts have a crucial role in accelerating the progression of intrahepatic cholangiocarcinoma and in promoting resistance to therapy through interactive autocrine and paracrine signaling pathways that promote malignant cell proliferation, migration, invasiveness, apoptosis resistance and/or epithelial-mesenchymal transition. These changes correlate with aggressive tumor behavior. Hypoxic desmoplasia and aberrant Hedgehog signaling between stromal myofibroblastic cells and cholangiocarcinoma cells are also critical modulators of intrahepatic cholangiocarcinoma progression and therapy resistance. A novel strategy has been developed to achieve improved therapeutic outcomes in patients with advanced intrahepatic cholangiocarcinoma, based on targeting of multiple interactive pathways between cancer-associated myofibroblasts and intrahepatic cholangiocarcinoma cells that are associated with disease progression and poor survival. Unique organotypic cell culture and orthotopic rat models of cholangiocarcinoma progression are well suited to the rapid preclinical testing of this potentially paradigm-shifting strategy.