Antibody-drug conjugates (ADCs) are synthesized by conjugating monoclonal antibodies with linkers and cytotoxic drugs. This conjugation harnesses the highly specific targeting capabilities of antibodies along with the potent cytotoxic effects of the drugs, demonstrating significant efficacy in the treatment of breast cancer. Nonetheless, the extensive clinical application of ADCs has revealed instances of resistance in breast cancer patients. In this paper, we provide a comprehensive overview of the structure and mechanism of ADCs, along with their current applications in the treatment of breast cancer. We categorize the mechanisms of ADC resistance into several distinct types: reduction in target antigen-antibody binding, impaired internalization and transport pathways of ADCs, dysfunctional lysosomal activity, abnormal payload release, tumor insensitivity to the payload, and the involvement of Cyclin. Additionally, we discuss the current challenges associated with ADC resistance, ongoing research into novel ADCs, and potential combination treatment strategies.