An article published in CANCER RESEARCH investigates the role of different doses for sorafenib in hepatocellular carcinoma resistance and response mechanisms. Acquired evasive resistance is currently the main drawback of the tyrosine kinase inhibitor (TKI) sorafenib for hepatocellular carcinoma (HCC). Recent findings suggest that sorafenib resistance may have a reversible phenotype. In addition, the lack of response is thought to be due to a progressive decrease in plasma levels of sorafenib. In the present study, the Hep3B HCG in situ human transplantation tumor model was used to investigate possible mechanisms of reversible sorafenib resistance in locally advanced hepatocellular carcinoma. Tissue and plasma sorafenib metabolism levels, downstream antitumor targets and toxicity were examined during treatment and progressively higher doses of sorafenib therapy. Consistent with the emergence of drug resistance, drug levels decreased significantly over time in both sorafenib-treated mice (30 mg/kg); and more substantial changes were observed in tissues than in blood. The rash also correlated with drug levels and its severity tended to decrease over time. The changes in drug levels appear to be partially tumor-associated to tumor-induced CYP3A4 metabolism, and the body does not develop resistance to early treatment. An increase in sorafenib dose from 30 mg/kg to 60 mg/kg improves antitumor efficacy but worsens survival due to excessive weight loss. Microvascular density is inhibited by sorafenib treatment while remaining stable over time and at increasing doses. Sorafenib-induced tumor CYP3A4 is a novel mechanism for overall drug level changes, but the overall decreased sorafenib levels may be only a minor resistance mechanism. Escalating doses may be an effective treatment strategy with manageable toxicity.