The rule of three describes three steps which are needed for an optimal control of postoperative nausea and vomiting (PONV). Firstly, patients at high risk of PONV need to be identified. Knowledge about predictive factors may help to identify patients who may best profit from prophylaxis and those where prophylaxis is not worthwhile since the baseline risk is too low. Secondly, for high-risk patients a low emetogenic anaesthesia technique should be chosen, and thirdly, these patients should additionally receive a prophylactic antiemetic cocktail. At present, butyrophenones (e.g. droperidol), 5-HT(3) receptor antagonists ("setrons") and steroids (e.g. dexamethasone) are the most rational choices for the antiemetic cocktail. Although there is strong evidence that there is an additive effect when these antiemetics are combined, economic constraints may influence the number of antiemetics that are eventually chosen. Identification of high-risk patients remains the most difficult part of the rule of three. Risk scores have been proposed and have been widely implemented in clinical practice. The sensitivity and specificity of such scores, however, remain particularly unsatisfactory. Unless more reliable risk scores are developed, aggressive treatment of established PONV symptoms may be more useful and more cost-effective than prophylaxis for many patients.