Neurological disorders frequently present with perplexing and alarming psychiatric symptoms, notably psychosis. While some neurologists may refer patients with psychotic symptoms to psychiatrists, others manage these conditions themselves, necessitating a comprehensive understanding of antipsychotic treatments. This chapter provides an overview of the evolution of antipsychotic medications, their efficacies, indications, adverse effects, and some special considerations, empowering neurologists to initiate treatment and coordinate long-term management. The discovery of chlorpromazine marked a turning point in psychiatric treatment, transforming the management of psychosis from ineffective institutionalization to targeted pharmacotherapy. However, while first-generation antipsychotics (FGAs) controlled positive symptoms, they often exacerbated negative symptoms and introduced distressing side effects. These limitations highlighted the need for more effective treatments, leading to the development of second-generation antipsychotics (SGAs) and many other options. SGAs, modeled after clozapine, offer improved safety profiles with lower risks of extrapyramidal symptoms (EPS) and enhanced efficacy in addressing negative and cognitive symptoms. Notably, clozapine remains the only antipsychotic approved for reducing suicidality in schizophrenia. Other antipsychotics available in the United States are also discussed in this chapter, with details regarding various formulations (e.g., long-acting injectables). Special populations, including pregnant women, children, and those with Parkinson’s disease psychosis, require particular consideration. Generally, benefits from treatment for psychosis outweigh the risks even in pregnancy. In children, some SGAs are approved for adolescents, though prepubescent use remains largely off-label. Parkinson’s disease patients benefit from pimavanserin, a nondopaminergic antipsychotic, representing a major advance in pharmacotherapy for this vulnerable group. The future of antipsychotic therapy is promising with ongoing research into novel mechanisms. As the field evolves, the focus remains on treating patients with psychotic symptoms while minimizing unwanted effects, paving the way for innovative interventions in primary and secondary psychosis.