The therapeutic landscape of acute myeloid leukemia (AML) has changed substantially over the past decade with the incorporation of molecularly targeted agents, lower-intensity venetoclax-based regimens, and increasingly refined genetic risk stratification. Among these advances, the combination of venetoclax with hypomethylating agents has become a pivotal treatment backbone for older or medically unfit patients with newly diagnosed AML, producing higher remission rates and longer survival than hypomethylating-agent monotherapy. However, venetoclax-based therapy is not curative for most patients. Primary resistance, incomplete eradication of leukemia stem and progenitor populations, lineage-associated drug tolerance, clonal evolution, and short survival after relapse have revealed major limitations of this approach. These challenges define the emerging post-venetoclax era of AML therapy. In this setting, treatment development is shifting from empiric intensification toward rational, biomarker-guided strategies that combine venetoclax-based backbones with targeted inhibitors of FLT3, IDH1/2, menin-dependent transcriptional programs, and other disease-specific vulnerabilities. At the same time, adverse-risk entities such as TP53-mutated AML continue to show limited benefit from venetoclax-based therapy, underscoring the need for alternative therapeutic frameworks. This review summarizes the clinical impact of venetoclax-based therapy, the biological and clinical mechanisms underlying treatment failure, and emerging strategies designed to improve outcomes after or beyond venetoclax exposure. We particularly highlight molecularly guided triplet regimens, menin inhibition, salvage approaches after hypomethylating-agent/venetoclax failure, measurable residual disease-guided treatment adaptation, and unresolved challenges in trial design, toxicity management, and patient selection. Understanding AML therapy through the lens of the post-venetoclax era may provide a practical framework for integrating targeted agents into precision treatment algorithms.