Some patients continue to struggle with delusions, hallucinations, disorganization, or severe negative/cognitive symptoms despite multiple antipsychotic trials. Treatment-Resistant Psychosis reframes these cases as solvable clinical puzzles with systematic steps—re-verification, precision pharmacology, neuromodulation options, psychosocial intensification, and safety/medical optimization. We begin by confirming the construct: accurate diagnosis (schizophrenia spectrum vs. mood with psychosis vs. substance/medical), true dose/duration/adherence, and confounders such as stimulant use, cannabis potency, anticholinergic burden, sleep apnea, autoimmune or seizure disorders, and sensory deficits. From there, we map a clozapine-first mindset: evaluate candidacy, anticipate barriers, and make monitoring feasible; when clozapine is not viable or is partial, layer long-acting injectables, targeted adjuncts, and evidence-based psychosocials. We emphasize negative and cognitive domains that drive disability—energy, initiative, processing speed—where cognitive remediation, supported employment/education, and structured routines often outperform dose escalations. Neuromodulation (ECT in select scenarios; emerging approaches in trials) is positioned within safety and consent frameworks. Medical health is non-negotiable: metabolic syndrome, tobacco use, sleep disturbance, and inactivity magnify relapse and mortality; a cardio-metabolic care bundle belongs in every plan. Engagement tactics—peer support, ACT/FACT teams, family psychoeducation—stabilize contact and reduce crisis cycling. Measurement must reflect real life: role goals, side-effect burden, and safety events sit alongside symptom scales. With disciplined troubleshooting and reliable follow-through, Treatment-Resistant Psychosis, shared learning at a treatment-resistant psychosis conference, and decisive steps in clozapine care can convert “stuck” trajectories into forward movement.