Chronic vascular inflammation is regarded as a crucial aspect of cardiovascular disease. However, the elicitors of this inflammatory response in the vessel wall are currently not well understood. Excessive amounts of cholesterol, an abundant and fundamental lipid molecule in mammalian cells, can initiate the development and progression of atherosclerosis. Accumulation of cholesterol in early atherosclerotic lesions results in the formation of macrophage foam cells, and crystalline cholesterol is found as a characteristic of advanced atherosclerotic plaques. Cholesterol crystals can activate the NLRP3 inflammasome, a multimolecular signaling complex of the innate immune system, resulting in caspase-1 mediated activation and secretion of proinflammatory interleukin-1 family cytokines. Furthermore, crystalline cholesterol is believed to induce plaque rupture by physical disruption of the fibrous cap covering atherosclerotic lesions. Here we review the effect of cholesterol deposition and crystallization on inflammatory responses in cardiovascular diseases.