The ethics of neuroleptic discontinuation in clinical and research settings are currently a topic of much discussion. The issues underlying this debate are complicated by the fact that these medications can be fairly effective in managing the symptoms and preventing relapse in schizophrenia and other psychotic disorders, yet these drugs have therapeutic limitations and their prolonged use is associated with a risk of serious, potentially persistent side-effects such as tardive dyskinesia. Over the past 47 years, the public perception about the value of neuroleptics has undergone dramatic shifts, based partly on the data available at different time periods. The risk-benefit ratio is better for the atypical antipsychotics compared to the conventional ones, but long-term experience with the newer agents has been limited. At present, a prudent strategy for most clinical and research purposes is to gradually taper the medications in clinically stable, carefully selected, consenting subjects to the lowest doses on which individual patients can be effectively maintained. In this article we discuss clinical, research, and ethical aspects of neuroleptic discontinuation. It is critical to protect potentially vulnerable patients with serious mental illnesses, while allowing them to benefit from appropriate investigations.