Hepatocellular carcinoma (HCC) has traditionally been an attractive system for cancer research because many animal HCC models are available. It is well known that liver tumors in animals can be induced by many different protocols, such as chronic hepatitis viral infections, carcinogens, toxins, steroid hormones, and dietary intervention. Although these different inducers have different cellular targets and modes of cytotoxic effects, their common denominator is the formation of reactive oxygen species (ROS). In this review, we present compelling evidence to support the hypothesis that ROS play important roles in hepatocarcinogenesis and the associated upregulation of drug resistance gene expression.