Background: Approximately 20% of patients with chronic myeloid leukemia and most patients with BCR-ABL-positive acute leukemia demonstrate resistance to imatinib mesylate resulting in treatment failure or suboptimal patient outcomes. We hypothesize that monitoring the development of cellular stress in BCR-ABL cells incubated with tyrosine kinase inhibitors (TKI) can be used as an early marker for determining the effects of the drugs on the cancer cells enabling rapid identification of drug-resistance and facilitating change to more effective therapies. Methods: The dielectric permittivities of non-leukemic peripheral blood mononuclear cells (PBMCs) and BCR-ABL cell lines known to be resistant (K562R and BaF3/T315I) or sensitive (K562 and HL60/BCR-ABL) to different TKIs were measured in the presence of imatinib (IMT), dasatinib (DAS), nilotinib (NIL), or ponatinib (PON) using the Z-Sense differential impedance sensing platform to record any changes in cellular stress. We also performed similar measurements on PBMCs from newly diagnosed CML patients exposed in vitro to the same TKIs. Results: Non-leukemic PBMCs showed no significant background levels when incubated with the following TKI concentrations: IMT (5 mg/mL), DAS (5 mg/mL), NIL (2.5 mg/mL), and PON (5 ng/mL). Normalized dielectric responses for all drug-resistant cell lines showed no change in value similar to control runs where no drugs were added. In contrast, all responses obtained for cell lines sensitive to these same TKIs were immediate and continuously decreased in value over time compared with resistant cell lines (p<0.01). All sensitivities were confirmed by MTT assay. Notably, the response of BaF3/T315I cells to PON was easily distinguished from the responses to IMT, DAS, and NIL. Of significance, all responses of BCR-ABL(+) patient blood to the four TKIs measured prior to commencing therapy were qualitatively similar to sensitive cell line measurements and subsequently confirmed to respond to IMT therapy. Conclusions: Drug-sensitive BCR-ABL(+) cells can be readily distinguished from drug-resistant cells without cell culturing in less than 60 minutes by monitoring the development of cellular stress in response to TKI drugs using differential impedance sensing.