<p>Antibody–drug conjugates (ADCs) are an innovative approach in cancer therapy, combining the specificity of monoclonal antibodies (mAb) with the cytotoxic effect of chemotherapy agents. Despite the remarkable efficacy demonstrated in clinical studies, primary and secondary resistance to ADCs represent a concern and a significant challenge. Known resistance mechanisms mainly involve the targeted tumor antigen; the internalization, trafficking, and cleavage processes; the cytotoxic payload; and the intrinsic tumor cell dynamics of cell death and cell signaling. Key strategies to overcome these resistance mechanisms include the use of antibodies targeting the same antigen but with different payloads, developing dual-payload ADCs that target multiple cellular pathways, switching from non-cleavable to cleavable linkers, and combining ADCs with other therapies such as immune checkpoint inhibitors and antiangiogenic agents. By improving our understanding of what underlies the mechanisms of resistance to ADCs and implementing and studying systems to overcome these mechanisms, as well as using innovative therapeutic combinations, ADCs have the potential to continue to play a fundamental role in the treatment of tumors, especially refractory ones, providing patients with more effective and long-lasting therapeutic options, as well as better outcomes.</p>