Hepatocellular carcinoma (HCC) is one of the most prevalent human cancers all over the world. Sorafenib is the only first line proved treatment for advanced HCC patients. However, the emergence of sorafenib resistance impacts on the efficacy of HCC treatment, which can be primary or acquired (primary sensitive, and resistant late during treatment process). At present, the mechanism of sorafenib resistance is not clear yet, which can be related to the aberrations in genetics and phenotype of HCC cells and the modifications in tumor microenvironment. The autophagy, epithelial-mesenchymal transition (EMT), ferroptosis, and tumor-initiating cells (T-ICs) phenotype of HCC cells, as well as exosomes and vessel co-option, have drawn much attentions in recent years. We summarized the progress of the related studies in this article.