Myocardial ischaemia can precipitate fatal arrhythmia, the leading cause of mortality in the western world. During ischaemia, cardiac myocytes swell rapidly. Such changes in cell volume radically alter the electrophysiology of these cells. Ischaemia also alters the potency of antiarrhythmic drugs, with the effectiveness of some antiarrhythmics being diminished. Conversely, the ideal antiarrhythmic would be 'switched on' by ischaemia. As well as making the drug more potent, this would minimize unwanted side-effects by targeting diseased tissue alone. In this article, Anthony Wright and Siân Rees discuss possible strategies for developing 'ischaemia-selective' antiarrhythmics. To date, research has focused on potentiation of antiarrhythmic action by membrane depolarization, as occurs during ischaemia. The authors suggest that cell swelling alters drug efficacy and propose that this could represent a new way of targeting ischaemia.