Drug interactions are ubiquitous but those with proven clinical relevance are much less common. Only when the combined effects of the interacting drugs are greater or less than the arithmetic sum of their individual actions can the event be considered a true interaction. This eliminates many candidate 'interactions' which in reality merely describe the summation of similar or opposing, but independent, drug effects. An appreciation of those drug interactions that really do matter can be best achieved by combining a practical knowledge of the pharmacological mechanisms involved with awareness of the most vulnerable patients (those with little reserve capacity) and the drugs associated with the greatest risk (those with a narrow therapeutic index). This review follows these guidelines and provides an account of well documented drug interactions categorised according to mechanism.