Evidence-based treatment guidelines for the management of difficult-to-treat schizophrenia recommend clozapine since many years due to its superior efficacy for treatment-resistant positive symptoms.According to different guidelines, achieving plasma clozapine levels of ≥350 ng/ml constitutes a minimum threshold requirement for establishing clozapine non-response in treatment-resistant schizophrenia (TRS). In the context of optimal dose finding, both external factors (i.e. Cytochrome P450 1A2 (CYP1A2) modulating comedication, tobacco smoking, caffeine intake)and internal factors (i.e. age, gender, ethnicity) have to be taken into consideration to guarantee optimal safety and efficacy of clozapine treatment. Several studies have consistently shown the need of continued clozapine maintenance treatment, where safely tolerated, due to its superior efficacy in TRS. Nevertheless, clozapine is associated with potentially burdensome or even life-threatening side-effects and in up to 60% of patients with TRS, clozapine fails to be effective. The aim of my talk is to summarize the current evidence regarding optimization of clozapine monotherapy as well as pharmacological and non-pharmacological strategies (i.e. ECT) for clozapine-resistance.