The chapter discusses the response-to-retention hypothesis of early atherogenesis, which posits that the retention of atherogenic lipoproteins within the arterial wall is the central pathogenic process. This hypothesis challenges the traditional view that various factors such as endothelial injury, lipoprotein oxidation, and turbulent blood flow are necessary for atherogenesis. The authors argue that while these factors may contribute to atherogenesis, they are not individually necessary or sufficient to initiate lesions. Instead, they propose that the retention of lipoproteins, facilitated by molecules like proteoglycans, lipoprotein lipase (LpL), and sphingomyelinase (SMase), is the key event that triggers a cascade of events leading to lesion formation. They provide evidence that lipoprotein retention occurs rapidly and focally in susceptible arterial sites, and that this retention is sufficient to provoke cellular and matrix responses that accelerate atherogenesis. The chapter also outlines potential therapeutic strategies targeting lipoprotein retention and discusses the need for further research to understand the mechanisms involved in early atherogenesis.The chapter discusses the response-to-retention hypothesis of early atherogenesis, which posits that the retention of atherogenic lipoproteins within the arterial wall is the central pathogenic process. This hypothesis challenges the traditional view that various factors such as endothelial injury, lipoprotein oxidation, and turbulent blood flow are necessary for atherogenesis. The authors argue that while these factors may contribute to atherogenesis, they are not individually necessary or sufficient to initiate lesions. Instead, they propose that the retention of lipoproteins, facilitated by molecules like proteoglycans, lipoprotein lipase (LpL), and sphingomyelinase (SMase), is the key event that triggers a cascade of events leading to lesion formation. They provide evidence that lipoprotein retention occurs rapidly and focally in susceptible arterial sites, and that this retention is sufficient to provoke cellular and matrix responses that accelerate atherogenesis. The chapter also outlines potential therapeutic strategies targeting lipoprotein retention and discusses the need for further research to understand the mechanisms involved in early atherogenesis.