Herein, in light of the increasing demand to uncover drug resistance mechanisms, we dissected the function of FOXO3a-mediated ABCB1 in regulating TUBB3 feedback in the context of the development of multiple cross-resistance to chemically unrelated cancer chemotherapeutics in PTX-resistant cancer cells, and we extended this event to systemic drug-resistant tumor progression. This evidence concerns the gene FOXO3 and cancer.