Cholangiocarcinoma is rising in clinical importance because of increasing incidence, poor prognosis, and suboptimal response to therapy. Recent investigations into the underlying molecular mechanisms involved in cholangiocarcinogenesis and tumor growth have contributed greatly to our understanding of this disease. To review this topic, we discuss the molecular mechanisms in sections reflecting the unique features that allow cancer cells to develop and maintain a growth advantage. Through a better understanding of these mechanisms, improved and more specific diagnostic, therapeutic, and preventative strategies may be developed and hopefully improve the outcome of this devastating disease.