The emergence of multidrug resistance (MDR) in malignant tumors is one of the leading threats encountered currently in many chemotherapeutic agents. The overexpression of the ATP-binding cassette (ABC) transporters is involved in MDR. P-glycoprotein (P-gp)/ABCB1 is a member of the ABC transporter family that significantly increases the efflux of various anticancer drugs from tumor cells. Therefore, targeting P-gp with small molecule inhibitors is an effective therapeutic strategy to overcome MDR. Over the past four decades, diverse compounds with P-gp inhibitory activity have been identified to sensitize drug-resistant cells, but none of them has been proven clinically useful to date. Research efforts continue to discover an effective approach for circumventing MDR. This review has provided an overview of the most recent advances (last three years) in various strategies for circumventing MDR mediated by P-gp. It may be helpful for the scientists working in the field of drug discovery to further synthesize and discover new chemical entities/therapeutic modalities with less toxicity and more efficacies to overcome MDR in cancer chemotherapy.