Human ATP-binding cassette (ABC) transporter ABCG2 (BCRP) is critically involved in multidrug resistance of human cancer. This transporter exhibits broad substrate specificity toward structurally diverse compounds, as do other ABC transporters, such as ABCB1 (P-glycoprotein/MDR1), ABCC1 (MRP1/GS-X pump), and ABCC2 (MRP2/cMOAT). To gain insight into the relationship between the molecular structure of compounds and the ABCG2-mediated transport activity, we have developed a high-speed screening method to analyze the substrate specificity of ABCG2. In addition, we have developed an algorithm that analyzes QSAR to evaluate ABCG2-drug interactions. This chapter presents our strategy of transport mechanism-based molecular design to circumvent multidrug resistance of cancer.