Acute myeloid leukemia (AML) is a malignant disease derived from the bone marrow precursors of myeloid lineage Treatment options are rather limited, primarily based on chemotherapy, and often result in disease progression Recently, venetoclax-based therapies have transformed the frontline regimens of elderly patients and patients unfit for intensive chemotherapy. Despite its promising outcomes in clinical studies, multiple resistant subclones evolved during the treatment acting as a barrier in disease regression Understanding the venetoclax-resistance mechanisms and detecting the major determinants could reveal previously unrecognized novel perspectives for therapeutic strategies to improve patients’ outcomes. Moreover, performing high-throughput screenings with clinically approved drugs could reveal novel treatment options for resistant subclones of AML.