Biliary tract cancer (BTC) is a heterogeneous group of cancers, which is composed of intrahepatic cholangiocarcinoma (ICCA), extrahepatic cholangiocarcinoma (ECCA), gallbladder cancers and ampullary carcinomas. While all anatomic subgroups are treated uniformly, our understanding about the pathogenesis has allowed us to reason that each group represents a clinically and genetically diverse disease. The majority of patients present with locally advanced or metastatic disease, where the standard treatment is combination systemic cytotoxic chemotherapy with gemcitabine and cisplatin. While most receive a clinical benefit from chemotherapy, patients eventually progress where no standardized therapies are available in the refractory setting. With the use of next generation sequencing, we have come to understand that ICCA is a diverse genomic disease with many actionable alterations that may serve as potential therapeutic targets. Further studies investigating the role of novel targeted agents (as a single agent or with combination chemotherapy) will hopefully provide additional treatment options for this highly lethal disease.