A strong relationship between exposure to sorafenib and hand-foot skin reaction has been observed in multiple clinical studies. By developing a better understanding of the causes of sorafenib pharmacokinetic variability we can better address approaches to reduce this dose-limiting toxicity. Therefore, we developed a physiologically based pharmacokinetic (PBPK) model of sorafenib and its two main metabolites which accounted for drug transporters, hepatic metabolic enzymes, and intestinal β-glucuronidase. The model was evaluated using uncertainty and sensitivity analysis to better understand the pharmacokinetic variability observed in wild-type and transporter knock-out mice.