Introduction: Cholangiocarcinoma (CCA) is an aggressive primary liver malignancy with abysmal prognosis and increasing global incidence. Individuals afflicted with CCA often remain asymptomatic until late stages of disease, resulting in very limited possibilities for therapeutic intervention. The emergence of numerous preclinical models in vitro and in vivo has expanded the tool kit for CCA researchers; nonetheless, how these tools can be best applied to understand CCA biology and accelerate drug development requires further scrutiny. Areas covered: The paper reviews the literature on animal and organoid models of CCA (available through PubMed between September 2020 and January 2021) and examines their investigational role in CCA therapeutics. Finally, the potential of these systems for screening therapeutics to improve CCA patient outcomes is illuminated. Expert Opinion: The expansion of CCA models has yielded a diverse and interesting tool kit for preclinical research. However, investigators should consider which tools are best suited to answer key preclinical questions for real progress. A combination of advanced in vitro cell systems and in vivo testing will be necessary to accelerate translational medicine in cholangiocarcinoma.