The purpose of this review is to highlight some important issues regarding current centrally acting antitussive drugs as well as discuss the implications of these matters on the development of future cough suppressants. Drugs that act in the central nervous system to inhibit cough are termed centrally acting and this designation is based exclusively on evidence obtained from animal models. This classification can include drugs that act both at peripheral and central sites following systemic administration. These drugs are intended to reduce the frequency and/or intensity of coughing resulting from disorders of any etiology. There are a number of central cough suppressants identified by their efficacy in animal models and the most prominent of these are codeine and dextromethorphan. Although the exact neural elements on which these drugs act are currently unknown, they are thought to inhibit a functionally identified component of the central system for cough known as the gating mechanism. The efficacy of codeine and dextromethorphan in humans has recently been questioned. These drugs are less effective on cough induced by upper airway disorders than in pathological conditions involving the lower airways in humans. The reasons for this difference in antitussive sensitivity are not clear. We propose that sensory afferents from different regions of the airways actuate coughing in humans by antitussive sensitive and insensitive control elements in the central nervous system. This hypothesis is consistent with results from an animal model in which laryngeal and tracheobronchial cough had different sensitivities to codeine. Other factors that may be very important in the action of central antitussive drugs in humans include the role of sensations produced by a tussigenic stimulus as well as plasticity of central pathways in response to airway inflammation. Resolution of these issues in the human will be a challenging process, but one which will lay the foundation for the development of more effective cough suppressants.