The incidence of hepatocellular carcinoma (HCC) is still on the rise in North America and Europe and is the second leading cause of cancer-related mortality. The treatment of HCC varies, with surgery and locoregional therapy (LRT) such as radiofrequency ablation and transcatheter arterial chemoembolization, and radiation therapy being the primary treatment. Currently, systemic therapy with molecular-targeted agents and immune checkpoint inhibitors (ICIs) is becoming a major treatment option for the unresectable HCC. As the HCC after LRT or systemic therapy often remains unchanged in size and shows loss of contrast effect in contrast-enhanced CT or MRI, the response evaluation criteria in solid tumors (RECIST) and World Health Organization criteria, which are usually used to evaluate the treatment response of solid tumors, are not appropriate for HCC. The modified RECIST (mRECIST) and the European Association for the Study of the Liver (EASL) criteria were developed for HCC, with a focus on viable lesions. The latest 2018 edition of the Liver Imaging Reporting and Data System (LI-RADS) also includes a section on the evaluation of treatment response. The cancer microenvironment influences the therapeutic efficacy of ICIs. Several studies have examined the utility of gadoxetic acid-enhanced MRI for predicting the pathological and molecular genetic patterns of HCC. In the future, it may be possible to stratify prognosis and predict treatment response prior to systemic therapy by using pre-treatment imaging findings.