In chronic myeloid leukemia BCR-ABL1 mutations and activation of additional pro-oncogenic pathways cause therapy resistance. Drug combinations covering a broad range of targets may overcome resistance.We investigated a compound that inhibits proliferation and survival of tyrosine kinase inhibitor-resistant BCR-ABL1+ cell lines. Succesful drug-combinations blocked multiple signalling cascades and molecules, including STAT3 and STAT5. Furthermore, combined targeting of STAT3 and STAT5 by shRNA and STAT5-targeting drugs also resulted in synergistic growth-inhibition, pointing to a new efficient concept of combinatorial STAT3 and STAT5 inhibition. Combined targeting of STAT3, STAT5, and heme-oxygenase-1 overcomes resistance in cell lines and whether such drug-combinations are effective in tyrosine kinase inhibitor-resistant patients with chronic myeloid leukemia should be elucidated.