Introduction: Approximately one-third of patients do not respond to treatment of positive symptoms with non-clozapine antipsychotics. Additionally, half of them show poor response to clozapine, electroconvulsive therapy, or other augmentation strategies [Masataka et all., 2022]. The need for new or adjunctive therapies in schizophrenia is caused by the severe impact of schizophrenia on the human personality and the relationship of these patients with the environment. Material and methods: The paper consists of the bibliographical assessment and some results with personal participation in clinical trials assigned to treatment of schizophrenia. Results and discussion: The first references to resistance in treatment appear in papers of Kane et al. (1988), then Meltzer (1997), Conley and Kelly (2001). The definitions in generally have included at least 2 courses of different antipsychotics at equivalent doses of chlorpromazine between 400–600 mg/day for a period of 4–6 weeks without clinical improvement, lack of good social or occupational functioning in the past 5 years, BPRS scale >45 and a score ≥ 4 on 2 of 4 positive symptoms. A new approach was approved by the Working Group Consensus Guidelines on Diagnosis and Terminology [Am J Psychiatry 2017] according to which the resistance criteria were divided into the positive, negative, cognitive or mixed domains. The pharmacologicalapproach have been focused on well known dopamine, hydroxytryptamine, NMDA, GABA or more recently, sigma receptors. Other studies addressed to adjunctive therapies like aspirin, pramipexole, minocycline, glycine, allopurinol, estradiol some of which showed poor while others showed more promising results. Conclusions: It seems that the receptors involved in the generation and maintenance of negative symptoms will be the predominant target of future therapies in schizophrenia.