The estrogen receptor (ER) pathway plays a crucial role in the development and progression of breast cancer. Endocrine therapy, which blocks the ER pathway, is highly effective but is limited by intrinsic and acquired resistance. Multiple mechanisms contribute to endocrine resistance, including deregulation of ER components, alterations in cell cycle and survival signaling, and activation of alternative pathways that provide tumors with alternative proliferative and survival stimuli. Increased expression or signaling of growth factor receptor pathways, particularly the EGFR/HER2 pathway, has been associated with both experimental and clinical endocrine therapy resistance. New treatment combinations targeting ER and growth factor receptor signaling, which block crosstalk between these pathways, have shown promising results in preclinical models. Recent clinical studies highlight the need to better identify patients whose tumors are most likely to benefit from these co-targeting strategies. The tumor microenvironment and host-associated mechanisms also play a role in endocrine resistance, with stromal cells, extracellular matrix, and soluble factors influencing the sensitivity of tumors to endocrine therapy. Clinical trials have tested the combination of endocrine therapy with growth factor receptor inhibitors, showing some success in specific patient populations. Further research is needed to confirm and expand these findings and to identify patients most likely to benefit from these strategies.The estrogen receptor (ER) pathway plays a crucial role in the development and progression of breast cancer. Endocrine therapy, which blocks the ER pathway, is highly effective but is limited by intrinsic and acquired resistance. Multiple mechanisms contribute to endocrine resistance, including deregulation of ER components, alterations in cell cycle and survival signaling, and activation of alternative pathways that provide tumors with alternative proliferative and survival stimuli. Increased expression or signaling of growth factor receptor pathways, particularly the EGFR/HER2 pathway, has been associated with both experimental and clinical endocrine therapy resistance. New treatment combinations targeting ER and growth factor receptor signaling, which block crosstalk between these pathways, have shown promising results in preclinical models. Recent clinical studies highlight the need to better identify patients whose tumors are most likely to benefit from these co-targeting strategies. The tumor microenvironment and host-associated mechanisms also play a role in endocrine resistance, with stromal cells, extracellular matrix, and soluble factors influencing the sensitivity of tumors to endocrine therapy. Clinical trials have tested the combination of endocrine therapy with growth factor receptor inhibitors, showing some success in specific patient populations. Further research is needed to confirm and expand these findings and to identify patients most likely to benefit from these strategies.