Precision medicine and immunotherapeutic approaches have gained popularity in oncological research over the last decade. Early clinical trials employing these techniques showed promising results, albeit phase III clinical trials showed sufficient clinical response rates in only a fraction of patients. Knowledge from subsequent translational studies imply the importance of targeting the tumor micro-environment to overcome resistance to immunotherapy. In these times of precision medicine, it is crucial to consider inter- as well as intratumoral heterogeneity. Single cell analysis is the leading-edge technology that enables us to better define tumor cell community and to identify new possible targets for immunotherapy or combination treatments. This review focuses on the approach of single cell analysis in the context of immunotherapy in liver cancer, which includes rationales to study hepatocellular carcinoma biology at a single cell level. Personalized medicine will highly benefit from the resolution that single cell technologies provide to discover new therapeutic innovations and understand resistance mechanisms.