We identified ADC payloads that were not substrates of either P-gp or ABCG2—notably the duocarmycin series and PNU-159682, which were among the most cytotoxic of all the toxins studied in a panel of 99 cancer cell lines—and suggest that these compounds be prioritized as future ADC payloads due to the potential for reduced susceptibility to transporter-mediated acquired resistance. This evidence concerns the gene PGP and cancer.