Peter Libby's article reviews the historical development of the understanding of inflammation in atherosclerosis. Initially, atherosclerosis was thought to be primarily a cholesterol storage disease. However, over the past few decades, the role of inflammation in atherogenesis has become increasingly recognized. The discovery that cytokines play a crucial role in inflammatory signaling has provided a mechanistic link between traditional risk factors and the altered biology of the arterial wall that leads to atherosclerosis. The immune response, including both innate and adaptive immunity, is now understood to be a key driver in the progression of atherosclerotic lesions and their thrombotic complications. The article highlights several key milestones in this scientific journey. Egyptian papyri from 5000 years ago described heat and redness as signs of disease, and Aulus Cornelius Celsus defined the cardinal signs of inflammation in the first century. Rudolf Virchow recognized the inflammatory nature of arteriosclerotic plaques in the 19th century, suggesting that atherogenesis is an active process rather than a passive accumulation of lipid deposits. The advent of immunology and the discovery of adhesion molecules by vascular endothelial cells have further elucidated the initiation and progression of atherosclerotic lesions. The article also discusses the role of mononuclear phagocytes, such as macrophages and T lymphocytes, in atherogenesis. Macrophages, which are the primary leukocytes in atheromas, contribute to the formation of the necrotic core and the thrombotic complications of atherosclerosis. T lymphocytes, while present in lower numbers, play a crucial role in regulating the inflammatory response through the production of cytokines like IFN-γ. The special case of allograft vasculopathy, where atherosclerosis develops rapidly in the absence of traditional risk factors, further underscores the importance of immune mechanisms in atherosclerosis. The discovery that adaptive immunity is a key element in this process has led to the development of biomarkers of inflammation, such as C-reactive protein (CRP), which can predict cardiovascular events in healthy individuals. Finally, the article discusses the clinical implications of these findings, including the use of statins and anti-inflammatory therapies to reduce cardiovascular risk. The JUPITER trial, which demonstrated the effectiveness of statins in individuals with elevated CRP levels, is highlighted as a significant step forward in translating these biological insights into clinical practice. The ongoing research aims to identify additional targets to break the cycle of inflammation and improve outcomes in atherosclerosis.Peter Libby's article reviews the historical development of the understanding of inflammation in atherosclerosis. Initially, atherosclerosis was thought to be primarily a cholesterol storage disease. However, over the past few decades, the role of inflammation in atherogenesis has become increasingly recognized. The discovery that cytokines play a crucial role in inflammatory signaling has provided a mechanistic link between traditional risk factors and the altered biology of the arterial wall that leads to atherosclerosis. The immune response, including both innate and adaptive immunity, is now understood to be a key driver in the progression of atherosclerotic lesions and their thrombotic complications. The article highlights several key milestones in this scientific journey. Egyptian papyri from 5000 years ago described heat and redness as signs of disease, and Aulus Cornelius Celsus defined the cardinal signs of inflammation in the first century. Rudolf Virchow recognized the inflammatory nature of arteriosclerotic plaques in the 19th century, suggesting that atherogenesis is an active process rather than a passive accumulation of lipid deposits. The advent of immunology and the discovery of adhesion molecules by vascular endothelial cells have further elucidated the initiation and progression of atherosclerotic lesions. The article also discusses the role of mononuclear phagocytes, such as macrophages and T lymphocytes, in atherogenesis. Macrophages, which are the primary leukocytes in atheromas, contribute to the formation of the necrotic core and the thrombotic complications of atherosclerosis. T lymphocytes, while present in lower numbers, play a crucial role in regulating the inflammatory response through the production of cytokines like IFN-γ. The special case of allograft vasculopathy, where atherosclerosis develops rapidly in the absence of traditional risk factors, further underscores the importance of immune mechanisms in atherosclerosis. The discovery that adaptive immunity is a key element in this process has led to the development of biomarkers of inflammation, such as C-reactive protein (CRP), which can predict cardiovascular events in healthy individuals. Finally, the article discusses the clinical implications of these findings, including the use of statins and anti-inflammatory therapies to reduce cardiovascular risk. The JUPITER trial, which demonstrated the effectiveness of statins in individuals with elevated CRP levels, is highlighted as a significant step forward in translating these biological insights into clinical practice. The ongoing research aims to identify additional targets to break the cycle of inflammation and improve outcomes in atherosclerosis.