Continuous ST-segment monitoring has been used to detect acute myocardial ischemia, determine the success of the reperfusion therapy, and predict outcomes in both research and a variety of clinical settings. However, analyzing the abundant electrocardiography (ECG) data recorded using continuous multilead ST-segment monitoring techniques is time consuming and requires expertise. Experienced data interpreters in dedicated ECG core laboratories handle many continuous ECG data records from large clinical trials. Little information on measurement issues for computer-assisted ST-segment analysis is available for individual investigators. Unsupervised or inexperienced computer analysis of ST-segment deviations can, under certain circumstances, yield invalid or unreliable summary indices. The goal of this article is to discuss basic ST-segment measurement principles in evaluating acute myocardial ischemia and methodological issues surrounding the use of computer-assisted ST-segment analysis for continuous ECG data. Variables affecting ST-segment measurements will be examined. Sources and examples of variability for these potential errors will be identified.