Advanced hormone receptor-positive breast cancer, representing the majority of metastatic cases, now benefits from genomic-driven treatment selection. Researchers have identified specific resistance mechanisms including CDK4/6, PI3K, and AKT pathway alterations that predict response to targeted inhibitors, while transcriptomic profiling helps sequence newer estrogen receptor degraders and antibody-drug conjugates. This precision approach represents a significant evolution from traditional hormone therapy alone. The genomic-guided strategy addresses a critical clinical challenge: virtually all patients eventually develop endocrine resistance, often through multiple molecular pathways simultaneously. By identifying driver mutations upfront, oncologists can now anticipate resistance patterns and select combination therapies accordingly. The integration of tumor microenvironment factors adds another layer of personalization, potentially explaining why identical genomic profiles can yield different treatment responses. However, the complexity of implementing comprehensive genomic testing in routine practice remains substantial, requiring specialized infrastructure and interpretation expertise. The real-world impact will depend on whether this sophisticated molecular profiling translates into meaningfully extended survival and quality of life for the 70% of breast cancer patients with this subtype, rather than simply more treatment options.