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The last three years have seen remarkable progress in comprehending predisposing factors and upgrading our treatment arsenal concerning hepatocellular carcinoma (HCC). Until recently, there were no means to withstand the progression of viral hepatitis-associated liver cirrhosis to HCC. A deeper understanding of the molecular mechanism of the disease, the use of biomarkers, and the follow-up, allowed us to realize that conventional chemotherapy failing to increase survival in patients with advanced HCC tends to be exiled from clinical practice. Multi-kinase inhibitors (TKIs) such as sorafenib, lenvatinib targeting mainly the vascular endothelial growth factor receptors 1–3 VEGFRs 1–3 provided until recently the standard of care for these patients, as first- or second-line treatment. Since May 2020, the atezolizumab plus bevacizumab combination (immunotherapy plus anti-VEGF) has become the new reference …