The article revisits the role of ATP-binding cassette (ABC) transporters, particularly multidrug resistance protein 1 (MDR1, also known as P-glycoprotein or P-gp), in multidrug resistance (MDR) in cancer. Despite extensive research, the development of MDR1 as a therapeutic target has been unsuccessful due to the lack of appropriate tools for characterization and clinical development. However, recent advancements in technology and new data suggest that it is time to re-evaluate the role of ABC transporters in MDR. The authors highlight recent evidence indicating that ABC transporters play a significant role in drug resistance in various cancer types and at the blood-brain barrier. They discuss the structure and function of ABC transporters, their physiological roles, and their potential as therapeutic targets. The article also reviews the history of ABC transporters, the clinical trials of ABCB1 inhibitors, and the complex role of multiple transporters in MDR. Additionally, it explores the impact of transporter expression on drug bioavailability and brain penetration, as well as the potential of imaging techniques to assess transporter function in tumors. The authors conclude that while there is still much to learn, there is sufficient evidence to reconsider the investigation of ABC transporters in MDR, particularly in personalized medicine approaches.The article revisits the role of ATP-binding cassette (ABC) transporters, particularly multidrug resistance protein 1 (MDR1, also known as P-glycoprotein or P-gp), in multidrug resistance (MDR) in cancer. Despite extensive research, the development of MDR1 as a therapeutic target has been unsuccessful due to the lack of appropriate tools for characterization and clinical development. However, recent advancements in technology and new data suggest that it is time to re-evaluate the role of ABC transporters in MDR. The authors highlight recent evidence indicating that ABC transporters play a significant role in drug resistance in various cancer types and at the blood-brain barrier. They discuss the structure and function of ABC transporters, their physiological roles, and their potential as therapeutic targets. The article also reviews the history of ABC transporters, the clinical trials of ABCB1 inhibitors, and the complex role of multiple transporters in MDR. Additionally, it explores the impact of transporter expression on drug bioavailability and brain penetration, as well as the potential of imaging techniques to assess transporter function in tumors. The authors conclude that while there is still much to learn, there is sufficient evidence to reconsider the investigation of ABC transporters in MDR, particularly in personalized medicine approaches.