Objectives: The aim of this paper is to clearly describe the use of antipsychotics in off-label indications in terms of prevalence, the level of evidence of efficacy in individual indications, risks of use in the general population and the specifics of use in children and the elderly. Material and Methods: For the purposes of this research, a systematic and retrospective review of scientific and professional literature was made. Relevant therapeutic manuals, currently valid therapeutic guidelines, publications of professional associations and institutions, drug databases and other available sources were searched. Results: Antipsychotics with the highest prevalence of off-label use in general and special populations have been identified. The most significant off-label indications were identified and the level of evidence of efficacy and safety for each antipsychotic was presented. The benefits and risks of off-label use of antipsychotics and its specifics in children and the elderly are described. Conclusion: The off-label use of antipsychotics is highly prevalent in clinical practice despite the fact that the efficacy and safety have not been adequately evaluated. Undoubtedly, there are clinical situations in which it is rational to use an antipsychotic in the off-label indication, but always guided by medical evidence. There are small number of indications that have relatively strong evidence but for most they are limited. Vulnerable groups of patients, children and the elderly, are particularly exposed to unjustified off-label use of antipsychotics and are at increased risk with questionable therapeutic benefits. It is necessary to routinely and systematically collect data within the off-label application process in order to be able to determine, with greater reliability, the ratio of benefits and risks for future patients and the appropriateness of choosing such therapeutic approach.