ObjectiveTo systematically elucidate the resistance mechanism of targeted drug therapy for breast cancer and to discuss future direction of optimized treatment strategies. MethodA literature review on targeted therapy for breast cancer had been conducted based on recent domestic and international research. ResultsContemporary breast cancer targeted therapies mainly comprised human epidermal growth factor receptor 2 (HER2)-directed agents, CDK4/6 inhibitors, phosphatidylinositol 3-kinase/protein kinase B/mechanistic target of rapamycin pathway blockers, poly (ADP-ribose) polymerase inhibitors, and immune checkpoint modulators, etc. While these agents had conferred subtype-specific survival benefits, resistance developed through target mutations, compensatory signaling, epigenetic alterations, drug efflux pumps, among other mechanisms. Emerging strategies for reversing drug resistance included dual-targeted approaches (such as trastuzumab in combination with pertuzumab), dynamic monitoring of drug-resistant gene mutations by liquid biopsy, epigenetic modulators, etc. ConclusionsDrug resistance remains a key bottleneck limiting long-term efficacy of breast cancer targeted therapy. Future research should integrate multi-omics approaches to decipher tumor heterogeneity, implement combinatorial multi-target inhibition with real-time monitoring of multidimensional interventions, and leverage artificial intelligence to predict resistance evolution. This integrated strategy is expected to enable personalized combination therapies, ultimately overcoming drug resistance and improving patient survival outcomes.