Ambulatory ECG monitoring has become increasingly important in the diagnostic workup of patients investigated for chest pain and in the evaluation of patients with known ischemic heart disease. Following the demonstration of ischemic episodes not associated with anginal symptoms, the diagnosis of myocardial ischemia is based solely on the detection of ST segment shifts; however several conditions associated with non-ischemic ST segment changes during ambulatory ECG monitoring might potentially be misleading. These conditions include: 1) ST segment changes in the normal population: it is a rare finding in specifically designed studies that however are probably affected by a "pretest referral bias"; caution is therefore suggested in diagnosing ischemia when episodes of ST segment depression are mild (< 2 mm) and occur at high heart rates (> 120 beats/min); 2) postural changes, usually easily recognized by the typical "square" pattern of the ST segment trend; 3) ST segment changes related to respiratory manoeuvres, quite rare and usually mild; 4) ST segment changes due to drugs; 5) ST segment changes caused by rhythm and conduction disturbances. Lastly the significance of ST segment changes in patients with angina and normal coronary arteries is discussed, following recent observations of reduced coronary flow reserve and/or abnormal myocardial metabolism in a sizable proportion of these patients.