Treatment-resistant depression (TRD) represents a major clinical challenge and a distinct neurobiological syndrome within affective disorders. This chapter outlines the latest progress in therapeutic strategies, highlighting translational models, precision psychiatry, personalized therapeutic strategies, and computational tools. Traditional pharmacotherapy largely targets monoaminergic systems, especially serotonin, dopamine, and norepinephrine; however, with growing mechanistic insights into additional impairment, precision interventions are becoming feasible but remain constrained by clinical trial design, regulatory barriers, and access disparities. We aim not to revisit established advanced treatment strategies but to disseminate experimental developments that have shown enough promise in preclinical studies to spark scientific curiosity and inspire new TRD management strategies.