Optical coherence tomography (OCT) is a novel invasive imaging technology that allows in vivo assessment of the coronary wall with high resolution (approximately 15 micron). OCT offers a number of specific diagnostic features to study culprit lesions in patients suffering from acute coronary syndrome (ACS). Clinical OCT studies in patients presenting with ACS were able to confirm post mortem histopathology findings and shed light on the dynamic nature of atherosclerotic plaque formation, modification and rupture. OCT confirmed in vivo that the incidence of target lesion and remote TCFA varies with the clinical syndrome of the patients, being most pronounced in patients with acute myocardial infarction as compared to patients with stable angina. In culprit lesions where rupture of a fibrous cap has been documented, the fibrous cap thickness was in the range of 50 micron and macrophage density was elevated. Encouraging small scale clinical studies evaluated treatment effects in this population. OCT was used to demonstrate statin effects on fibrous cap thickness or the effects of different stent designs. The markedly improved image quality and user-friendliness of the second generation, Fourier-domain OCT, will allow large scale clinical application and thus, will increase our understanding of the pathophysiology and the prevention of ACS.