Abstract: Drug resistance is the main obstacle restricting the therapeutic efficacy of small-molecule drugs and has become a major challenge in global public health and cancer treatment. This article systematically reviews the major mechanisms of small-molecule drug resistance, including target modification, bypass signal activation, enhanced drug efflux, enzyme-mediated drug inactivation, and cell phenotypic transformation. It further focuses on the strategies to reverse drug resistance based on the above mechanisms. The relevant strategies include next-generation inhibitor development, allosteric inhibition, combination therapy, proteolysis-targeting chimeras (PROTACs), efflux pump inhibition, and antibody-drug conjugates (ADCs) as emerging technologies. By integrating the latest research advances in preclinical and clinical studies, this article aims to provide a theoretical basis and practical guidance for overcoming small-molecule drug resistance.