This volume evaluates the clinical patterns of resistance to sorafenib, the impact of trial design in the second-line setting and the current gold standard to define radiological resistance; describes the molecular mechanisms responsible for treatment resistance in HCC patients, including components of the immune system and tumor microenvironment; determines the role of the cancer stem cell phenotype in resistance; reviews the experimental models to study resistance; and addresses new approaches to overcome resistance to sorafenib, using successful examples from other malignancies.