Biliary tract cancers (BTC) are a relatively rare heterogeneous group of four to five anatomically distinct cancers whose prognosis is poor, even in the setting of attempted curative resection. Curative resection, in itself, is much less common than locally advanced unresectable and/or overt metastatic disease at presentation. Standard chemotherapy options are generally palliative for advanced BTC (aBTC), and recently the combination of gemcitabine with cisplatin has emerged as the standard-of-care providing a median overall survival of approximately one year. A movement toward molecularly based personalized cancer therapy has occurred in recent years, including for aBTC, with a number of pathways emerging as putative therapeutic targets. This review will briefly summarize the epidemiology, etiology, and general prognosis of BTC, then discuss the data supporting current standard cytotoxic treatments of aBTC, and proceed to focus on the molecular features of this heterogeneous set of diseases. Finally, we review strategies which will potentially improve our ability to individualize therapy and, ultimately, clinical outcomes in the future.