Hepatocellular carcinoma (HCC), cholangiocarcinoma, and pancreatic ductal adenocarcinoma (PDAC) are the most common primary hepatobiliary and pancreatic cancers and are associated with poor survival. With improvements in anticancer therapy during recent decades, assessment of treatment response has become more significant and different methods have been utilized in evaluating response to therapy. While conventional methods rely solely on size reduction, newer techniques focus on changes in tumor functional features as a response to treatment. In assessing HCC tumors response, WHO and RECIST only considered tumor shrinkage as a response to treatment. With the introduction of locoregional and molecular-targeted therapies in HCC treatment, the limitations of size-based criteria were addressed by development of new criteria that considered functional imaging parameters such as tumor enhancement. Functional criteria such as Choi, RECICL, EASL criteria, and mRECIST mostly focus on the viability/functionality of the tumor and are considered more accurate in assessing treatment response. In addition, new advanced technologies like CTPI, DWI, IVIM, MRS, MR-PWI, FDG-PET/CT, and PET/MRI can detect response at molecular level and can assess treatment response before any morphological changes take place. Similar to HCC, functional criteria using modalities like FDG-PET/CT, PET/MRI, DCE-MRI, and DWI are also being utilized in the evaluation of cholangiocarcinoma and PDAC in addition to conventional size criteria to detect early changes of treatment response.