The poor outcome of patients with non-surgically removable advanced hepatocellular carcinoma (HCC), the most frequent type of primary liver cancer, is mainly due to the high refractoriness of this aggressive tumor to classical chemotherapy. Novel pharmacological approaches based on the use of inhibitors of tyrosine kinases (TKIs), mainly sorafenib and regorafenib, have provided only a modest prolongation of the overall survival in these HCC patients. The present review is an update of the available information regarding our understanding of the molecular bases of mechanisms of chemoresistance (MOC) with a significant impact on the response of HCC to existing pharmacological tools, which include classical chemotherapeutic agents, TKIs and novel immune-sensitizing strategies. Many of the more than one hundred genes involved in seven MOC have been identified as potential biomarkers to predict the failure of treatment, as well as druggable targets to develop novel strategies aimed at increasing the sensitivity of HCC to pharmacological treatments.