In this review, we summarize the recent progress of the most clinically significant ABC transporters ABCB1, ABCG2, and ABCC1 that cause multi-drug resistance during cancer therapy, with the emphasis on novel small molecule compounds that are tested in preclinical and clinical studies, mainly on natural products, synthetic compounds, aiming to provide a wider perspective to understand the multidrug resistance and new strategies targeting ABC transporters in cancer treatment. The gene discussed is ABCG2; the disease is cancer.