Biliary tract cancers constitute approximately 3% of gastrointestinal malignancies with poor prognosis. Surgical therapy is the main form of treatment in localised disease; however, for patients with advanced stage or unresectable disease, locoregional and systemic chemotherapeutics are primary treatment options. Although the combination of gemcitabine and cisplatin is a standard regimen of choice, there are no consensus guidelines that help in choosing an appropriate second-line therapy. Substantial progress has been made in the past decade to understand the tumorigenesis and genetic landscape of each biliary tract cancer subtype, which facilitates precision medicine for this cancer. Common genes implicated in biliary tract cancer tumorigenesis include IDH1, IDH2, FGFR1, FGFR2, FGFR3, EPHA2, BAP1, ARID1B, ELF3, PBRM1, PRKACA, PRKACB, HER2, and BRAF. With the advancements in molecular pathogenesis of biliary tract cancer, especially in an era of personalised medicine, many questions are yet to be answered in advanced stages of the cancer: what subset of patients might benefit from second-line drugs, how to choose an optimal second-line regimen, and their effects on quality of life. This Review seeks to summarise available literature and discuss the potential second-line systemic therapy options for advanced biliary tract cancer on the basis of advancements of our knowledge on molecular pathogenesis and tumorigenesis.