Most strokes and heart attack are due to the rupture of an atherosclerotic plaque. Plaque compositional features depicted by in vivo imaging including high resolution MRI and VH-IVUS have been shown to provide complementary value to luminal stenosis in identifying higher-risk lesions. However, the predicting power is still low and additional biomarkers are needed. Under the physiological condition, plaque is subject to mechanical loading due to pulsatile blood pressure and flow. Plaque structure possibly fails if this loading exceeds its material strength. Therefore, critical mechanical conditions should be integrated with plaque compositional features for a more accurate vulnerability assessment. This talk will overview recent advancements in mechanics-based plaque vulnerability assessment, highlight current challenging and propose strategies that how this novel technique should be integrated with in vivo imaging for a refined risk stratification.