Correct actin cytoskeleton organization is vital in the liver organ homeostasis and disease control. Rearrangements of the actin cytoskeleton may play a vital role in the bile duct cells cholangiocytes. An abnormal actin network leads to aberrant cell morphology, deregulated signaling networks and ultimately triggering the development of cholangiocarcinoma (CCA) and paving the route for cancer cell dissemination (metastasis). In this review, we will outline alterations of the actin cytoskeleton and the potential role of this dynamic network in initiating CCA, as well as regulating the course of this malignancy. Actin rearrangements not only occur because of signaling pathways, but also regulate and modify cellular signaling. This emphasizes the importance of the actin cytoskeleton itself as cause for aberrant signaling and in promoting tumorigenic phenotypes. We will highlight the impact of aberrant signaling networks on the actin cytoskeleton and its rearrangement as potential cause for CCA. Often, these exact mechanisms in CCA are limited understood and still must be elucidated. Indeed, focusing future research on how actin affects and regulates other signaling pathways may provide more insights into the mechanisms of CCA development, progression, and metastasis. Moreover, manipulation of the actin cytoskeleton organization highlights the potential for a novel therapeutic area.