Acute Myeloid Leukemia (AML) is a clinically aggressive and molecularly heterogeneous hematologic malignancy characterized by poor long-term outcomes, largely due to high rates of relapse and therapeutic resistance. For decades, standard treatment has relied on cytotoxic chemotherapy and allogeneic hematopoietic stem cell transplantation; however, these approaches are limited by toxicity and incomplete disease eradication. Advances in genomic and molecular profiling have substantially reshaped the therapeutic landscape, enabling the development of targeted agents directed against key oncogenic drivers, including FLT3 and IDH1/2 mutations, as well as the anti-apoptotic protein BCL-2. These therapies, often used in combination with hypomethylating agents, have improved response rates, particularly in older or unfit patients. In parallel, immunotherapeutic strategies, such as antibody–drug conjugates, bispecific T-cell engagers, and cellular therapies, have been explored, although their efficacy in AML remains constrained by antigen heterogeneity and an immunosuppressive bone marrow microenvironment. Importantly, durable responses are frequently undermined by resistance mechanisms involving leukemia stem cell persistence, clonal evolution, metabolic reprogramming, and niche-mediated protection. Emerging therapeutic strategies emphasize rational combination regimens, targeting metabolic dependencies, and the integration of precision medicine approaches guided by multi-omics profiling and minimal residual disease assessment. In this review, we provide an integrated overview of current therapeutic strategies in AML, with a particular focus on mechanistic insights, resistance pathways, and future directions for improving clinical outcomes.