Cilia are microtubule-based organelles, extending from the plasma membrane into the extracellular environment, which are ubiquitously expressed in most cells, including the epithelial cells of the lung, oviduct, breast, prostate, kidney, pancreas, and liver. Cholangiocytes, the epithelial cells lining the biliary tree in the liver, contain primary cilia extending from their apical plasma membrane into the ductal lumen. The loss of primary cilia has been described in several malignancies, including cholangiocarcinoma (CCA), suggesting that the loss of cilia is a common occurrence in neoplastic transformation. CCA is usually diagnosed late and it is a lethal cancer with very limited therapeutic options. Therefore, it is imperative to identify novel targets that can lead to new therapeutic strategies for this devastating disease. The role of primary cilia in tumorigenesis is poorly understood. The mechanisms leading to deciliation in tumor cells as well as the consequences of such a loss remain understudied. We propose the dysregulation of microRNAs (miRNAs) in CCA cells induces the overexpression of HDAC6 resulting in ciliary resorption via destabilization of the ciliary axoneme. The loss of cilia induces proliferation, migration, and invasion, contributing to tumor progression. Therefore, we proposed cholangiocyte primary cilia normally detect signals that function as a tumor suppressor mechanism. Our studies suggest that restoration of primary cilia and/or their complex multisensory signals, i.e. ciliotherapies, may be a potential therapeutic approach for CCA and other malignancies.