High restenosis rates continue to plague the overall efficacy of percutaneous transluminal coronary balloon angioplasty (PTCA). It is not surprising that predictions of long-term success or failure of PTCA based on coronary angiography are of limited value because these images provide only a circumscribed view of the arterial lumen and offer little insight into underlying plaque morphologic characteristics. Coronary atherosclerotic lesions are quite diverse with respect to plaque characteristics (eccentricity, concentricity, and extent of fibrosis, necrosis, and calcification) and cardiac ischemic syndromes (stable angina, unstable angina, myocardial infarction, and sudden cardiac death). It could thus be expected that dissimilar plaques will respond differently to balloon dilatation, and that plaque morphologic features may play an important role in the immediate and long-term outcome after PTCA. Histologic evaluation of de novo atherosclerotic plaques underscores the heterogeneity of coronary atherosclerosis. From pathologic examination of human coronary arteries subjected to PTCA during life, expansion of the arterial circumference via medial damage is required for an effective increase in lumen size. Eccentric plaques and plaques with a large necrotic core are more likely to be successfully dilated compared to concentric, fibrotic lesions. Intravascular ultrasound studies of PTCA have supported histologic findings. Restenosis involves the complex interaction of growth factors and cytokines, cellular elements (endothelial cells, smooth muscle cells, platelets, and inflammatory cells), and the extent of arterial injury. The effects of underlying plaque morphologic features on the vascular biology of restenosis requires further clarification.