Many developed countries have experienced a significant decrease in the incidence of CVD over the last decades. At the same time there is accumulating evidence of changes in disease characteristics. Atherosclerotic plaques less frequently display traditional morphological features of vulnerability and endothelial erosion is becoming an increasingly important cause of thrombotic occlusion. It can be assumed that these changes to a large extent are explained by life style changes and improved medical treatment. The latter is most likely of particular importance for patients with established CVD receiving current state-of-the-art preventive therapy including statins. However, many of these patients still suffer from recurrent events. Does this mean that the underlying atherosclerotic disease has become unresponsive to statin treatment? The answer is probably both yes and no. No, because statin treatment will still prevent much of the lipid-driven inflammation that causes plaque vulnerability and discontinuation of treatment will increase risk for a CV event. Yes, because if lipid-driven inflammation is controlled by statins other disease mechanisms will surface with time and these are likely to be statin-unresponsive. Therefore, future research needs to focus on characterizing such statin-unresponsive disease mechanisms. Novel biomarkers and other diagnostics, as well as therapies targeting these mechanisms, need to be developed.