The integration of next-generation sequencing (NGS) and advanced cytogenetic diagnostics into routine clinical practice is reshaping frontline treatment of acute myeloid leukemia (AML) in both fit and unfit patients. Molecular profiling now enables personalized treatment strategies, particularly for patients harboring mutations in FLT3, IDH1, IDH2, KMT2A, and NPM1. Small molecule inhibitors, first reserved for relapsed/refractory disease, are increasingly used in the upfront setting. However, universal NGS testing at diagnosis is critical to identify eligible patients for these targeted therapies. In patients lacking actionable mutations, treatment can still be refined using karyotypic abnormalities or high-risk features suggestive of antecedent MDS. In our practice, we continue to use 7 + 3 induction for fit patients, adding midostaurin or quizartinib for FLT3-mutated AML, or gemtuzumab ozogamicin for core binding factor (CBF) AML expressing CD33. For patients with therapy-related AML or AML with myelodysplasia-related changes, CPX-351 is our standard induction approach. For unfit patients, we generally offer hypomethylating agents with venetoclax. In the presence of IDH1 mutations, we consider azacitidine combined with ivosidenib. If venetoclax is contraindicated or not tolerated, targeted therapies such as gilteritinib, ivosidenib, or enasidenib may be appropriate based on mutation profile. However, we try to identify clinical trials for all our patients at diagnosis. One of the more exciting recent developments is the emergence of menin inhibitors for patients with KMT2A rearrangements or NPM1 mutations. While several agents have received FDA approval or breakthrough status in the relapsed/refractory setting, they are now being actively studied as frontline options with promising results. When feasible, clinical trial enrollment should be considered for newly diagnosed patients with these alterations. As the therapeutic landscape for AML continues to evolve, timely molecular characterization is more essential than ever to optimize outcomes and select the most appropriate frontline strategy.