Morphological imaging techniques are typically used in the anti-cancer drug efficacy evaluation process. However, these techniques can evaluate the therapeutic efficacy only when the tumor shows anatomic changes—usually at later stages, when the therapeutic effects are poor. In contrast, molecular imaging allows noninvasive monitoring of tumor growth, assessment of drug metabolism, and evaluation of therapeutic efficacy at the molecular and cellular levels. Multimodality molecular imaging, which combines the advantages of various imaging modalities, provides even more comprehensive therapeutic efficacy assessment in preclinical and clinical studies. This review provides an overview of molecular imaging evaluation of therapeutic efficacy of the anti-tumor drugs in hepatocellular carcinoma (HCC) both in preclinical and clinical research, which holds great promise in guiding HCC treatment into the era of precision medicine.