The revolution of precision medicine is rapidly changing the way we diagnose and treat cancer. The wide availability of comprehensive molecular profiling has led to the rapid accumulation of a wealth of molecular data, and no medical oncologist can evade the task of translating tumor molecular information into clinical practice. The clinically, biologically and molecularly heterogeneous group of HPB cancers poses a particular challenge for precision oncology both in the curative-intent and in the advanced stage settings. This review provides a concise and practice-oriented summary of recent developments in molecular subtyping and precision treatment for pancreatic cancer, biliary tract cancers, and hepatocellular carcinoma. The authors strongly believe that novel tools of precision oncology such as molecular monitoring and complex integrated biomarkers will have very significant impact on the clinical management of HPB cancer in the foreseeable future.