ObjectiveTo systematically elucidate the resistance mechanism of targeted drug therapy for breast cancer and to discuss the future direction of optimized treatment strategies. MethodA literature review on targeted therapy for breast cancer had been conducted based on recent domestic and international researches. ResultsContemporary breast cancer targeted therapies maincomprised human epidermal growth factor receptor 2 (HER2)-directed agents, CDK4/6 inhibitors, phosphatidylinositol 3-kinase (PI3K)/protein kinase B (PKB/AKT) / mechanistic target of rapamycin (mTOR) pathway blockers, poly (ADP-ribose) polymerase inhibitors, and immune checkpoint modulators, etc. While these agents conferred subtype-specific survival benefits, resistance developed through target mutations, compensatory signaling, epigenetic alterations, drug efflux pumps, etc. Emerging reversal drug resistance strategies involved 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 will enable personalized combination therapies, ultimately overcoming drug resistance and improving patient survival outcomes.