Atherosclerosis is the main pathophysiological process underlying acute cardiovascular diseases. Life-threatening conditions, such as myocardial infarction and ischemic stroke, are provoked by the sudden rupture of vulnerable atherosclerotic plaques, characterized by thin, highly inflamed and collagen-poor fibrous cap. Whereas both innate and adaptive inflammation progressively emerged as driving force of this processes, less is known about the involvement of neutrophils (PMNs). Advances in laboratory techniques during the last two decades disclosed that PMNs play a crucial role in promoting plaque vulnerability by the release of different enzymes, such as gelatinases (matrix metalloproteinases) collagenases, elastase and myeloperoxidase. Accordingly, circulating levels of PMNs and their products have been investigated as potential markers of plaque instability in both primary and secondary prevention on cardiovascular diseases. In addition, the development of different classes of drugs targeting PMNs activation is emerging as an interesting field of research. This narrative review will provide an update on the role of PMNs in promoting plaque vulnerability also discussing the potential effects of therapeutic strategies targeting PMN on plaque vulnerability.