Acute coronary syndromes (ACS) frequently cause considerable morbidity and mortality with a high risk of further events within the following year, despite the use of percutaneous coronary intervention (PCI). Numerous studies have described the concept of acute, partial or complete thrombotic occlusion of the coronary artery, which occurs at the site of a friable atherosclerotic plaque with a lipidrich necrotic core and a ruptured overlying thin fibrous cap ("culprit lesion"). Moreover, this process appears independent of the severity of the underlying stenosis. Most of our knowledge about the morphological characteristics of culprit lesions has been obtained from necropsy studies of lesions at the extreme end of the ACS spectrum. The development of intravascular ultrasound (IVUS) with virtual histology (VH), using spectral analysis of the radiofrequency ultrasound backscatter signals to identify the components of atherosclerotic plaque, has allowed in-vivo delineation of the relative contributions of necrotic core and fibrous atheroma in unstable lesions. This evidence suggests that there may be variations in the morphology of plaques that rupture and promote thrombosis in ACS, rather than the traditionally accepted view that a common pathological mechanism is at play. This imaging modality, therefore, provides great potential for invivo information about the culprit lesion. In this review article, we explore the background and potential application of virtual histology to improve the invasive treatment of ACS patients.