Personalized medicine is an emerging field that provides novel approaches to disease's early diagnosis, prevention, treatment, and prognosis based on the patient's criteria in gene expression, environmental factors, lifestyle, and diet. To date, hepatocellular carcinoma (HCC) is a significant global health burden, with an increasing incidence and significant death rates, despite advancements in surveillance, diagnosis, and therapeutic approaches. The majority of HCC lesions develop in patients with liver cirrhosis, carrying the risks of mortality associated with both the tumor burden and the cirrhosis. New therapeutic agents involving immune checkpoint inhibitors and targeted agents have been developed for sequential or concomitant application for advanced HCC but only a tiny percentage of patients benefit from each approach. Moreover, clinicians encounter difficulties determining the most appropriate regimen for each patient. This emphasizes the need for a personalized treatment approach. In other words, patients should no longer undergo treatment based on their tumor's histology but depending on the distinct molecular targets specific to their tumor biology. However, the utilization of precision medicine in managing HCC is still challenging. This review aims to discuss the role of personalized medicine in diagnosing, managing, and defining the prognosis of HCC. We also discuss the role of liquid biopsy and their clinical applications for immunotherapies in HCC. More clinical studies are still necessary to improve the precision of biomarkers used in the treatment decision for patients with HCC.