The incidence of treatment resistance in schizophrenia (failure to respond to antipsychotic therapy) is about 20%. Factors that may contribute to it include non-adherence (non-compliance) to treatment, comorbid conditions and medication side-effects. The National Institute for Clinical Excellence recommends that clozapine be used for schizophrenia resistant to another atypical antipsychotic. Here we focus on patients who are also resistant to clozapine given in adequate dosage for sufficient duration. Switching from clozapine to a previously untried atypical (e.g. olanzapine, risperidone, quetiapine) might be of benefit in partial treatment resistance. In more difficult cases, augmentation of clozapine with benzamides (sulpiride, amisulpride) and anti-epileptics (lamotrigine) shows some success. In extreme treatment resistance, a strategy is recommended that combines the proven best drug for the particular patient and psychosocial treatments.