In the clinical practice, there are three different terms to designate schizophrenic patients who do not improve with antipsychotic medication: treatment-resistant, treatment-refractory and non-respondent patients. Treatment resistance is neither a synonym of chronicity nor of severity nor seriousness. Therefore, for a patient to be considered resistant, several points must be taken into account. These points are: a) whether the schizophrenia is primary or secondary; b) its nature; c) presence of previous substance abuse; d) treatment compliance and tolerance, and presence of minor neurological signs. The most widely accepted criteria to define pharmacological treatment resistance in schizophrenia were initially developed around 1988 by Kane. Nowadays, the BPRS and Independent Living Skills Survey (ILSS) are the scales used to assess the levels of lack or response or of treatment resistance. To attain a suitable therapeutic evolution in schizophrenics resistant to treatment in antipsychotic medication assays, the following guidelines must be considered: Identifying the symptoms clearly and using medication with a suitable dose and duration. Taking into account that treatment resistance can be mistaken for treatment intolerance, non-compliance to treatment, inappropriate social support or inappropriate psychosocial treatment. Using up all single therapeutic agents before applying multiple agents. Preventing extrapyramidal effects by means of an adequate choice of the primary treatment. Maintaining a positive therapeutic attitude.