Treatment-resistant depression (TRD) remains a major clinical challenge, affecting a signifi cant proportion of individuals diagnosed with major depressive disorder (MDD). Despite the availability of numerous antidepressant therapies, approximately one-third of patients fail to achieve remission after two or more adequate treatment trials. This review explores the critical role of animal models in understanding the neurobiological mechanisms underlying TRD and in developing more effective therapeutic strategies. Classical models such as the Forced Swim Test, Tail Suspension Test, and Learned Helplessness have provided foundational insights into depressive behaviors and antidepressant effi cacy. However, these models often fall short in replicating the treatment-resistant phenotype. Emerging models such as those based on telomere dysfunction, genetic vulnerability, and comorbid anxiety-depression phenotypes offer promising platforms for investigating novel interventions. Additionally, the augmentation of pharmacological treatments, such as the coadministration of bupropion with SSRIs or SNRIs, highlights potential pathways for overcoming treatment resistance. The review emphasizes the importance of integrating behavioral, neurochemical, and genetic approaches to improve the translational validity of preclinical models. Ultimately, refi ning these models is essential for identifying effective and personalized treatments for individuals suffering from TRD.