The vast majority of acute coronary events are attributed to rupture or erosion of high-risk or vulnerable plaques. Novel imaging techniques are being actively sought that can detect quiescent vulnerable features within coronary plaque and thereby identify populations at risk, monitor plaque progression, and target therapy appropriately. Optical coherence tomography is an intravascular imaging modality capable of detecting and characterizing coronary plaque in vivo. Recently, optical coherence tomography quantification of macrophage infiltration within atherosclerotic plaque ex vivo was demonstrated. Application of this technique to clinical practice yields a hybrid image incorporating plaque morphology with a measure of biologic activity. In a recently conducted clinical study assessing macrophage distributions in patients, evidence supporting both the vulnerable plaque model and the hypothesis of multifocal inflammatory risk, linked by the common thread of increased macrophage infiltration, has been found. These results suggest that elevated multifocal coronary macrophage content, present both in culprit lesions and at remote sites, serves as a background for heightened risk. Superimposed on this inflammatory background, local increases in macrophage content, particularly at the cap surface and at areas at high risk for rupture, further promote the instability of individual lesions.