This review provides an integrated overview of the dysregulated cellular metabolism in atherosclerosis and its therapeutic potential. It highlights the role of metabolic dysregulation in endothelial cells (ECs), vascular smooth muscle cells (vSMCs), macrophages, and T cells. The review discusses the complex metabolic cross-talk between these lesional cells and explores emerging technologies that can illuminate unknown aspects of metabolism in atherosclerosis. It also suggests strategies for targeting these underexplored metabolic alterations to mitigate atherosclerosis progression and stabilize rupture-prone atheromas. Key points include: 1. **EC Activation and Metabolism**: EC activation is initiated by disturbed fluid shear stress (FSS), leading to metabolic dysregulation and enhanced oxidative stress. Mechanosensitive pathways, such as YAP/TAZ and HIF1α, play crucial roles in EC metabolism and atherosclerosis progression. 2. **vSMC Phenotypic Modulation**: vSMCs contribute to plaque stability through the formation of a collagen-rich fibrous cap. Glucose utilization and glycolysis control vSMC dedifferentiation, while arginine and tryptophan metabolism influence vSMC phenotypes and vascular calcification. 3. **Macrophage Immunometabolism**: Macrophages exhibit plasticity, transitioning between pro-inflammatory and pro-resolving states. Dysregulated cholesterol metabolism in macrophages leads to foam cell formation and atherosclerosis progression. Glycolysis and oxidative phosphorylation (OXPHOS) in macrophages are critical for inflammation and its resolution. 4. **T Cell Metabolism and Autoimmunity**: T cells, particularly regulatory T (Treg) cells and helper T (Th) cells, play a crucial role in atherogenesis. Metabolic reprogramming in T cells affects their function and fate, with specific nutrients like glucose and amino acids influencing T cell responses in autoimmunity. The review emphasizes the need for precise and carefully considered therapeutic interventions to target these metabolic alterations, considering the potential risks and benefits of metabolic manipulation in atherosclerosis.This review provides an integrated overview of the dysregulated cellular metabolism in atherosclerosis and its therapeutic potential. It highlights the role of metabolic dysregulation in endothelial cells (ECs), vascular smooth muscle cells (vSMCs), macrophages, and T cells. The review discusses the complex metabolic cross-talk between these lesional cells and explores emerging technologies that can illuminate unknown aspects of metabolism in atherosclerosis. It also suggests strategies for targeting these underexplored metabolic alterations to mitigate atherosclerosis progression and stabilize rupture-prone atheromas. Key points include: 1. **EC Activation and Metabolism**: EC activation is initiated by disturbed fluid shear stress (FSS), leading to metabolic dysregulation and enhanced oxidative stress. Mechanosensitive pathways, such as YAP/TAZ and HIF1α, play crucial roles in EC metabolism and atherosclerosis progression. 2. **vSMC Phenotypic Modulation**: vSMCs contribute to plaque stability through the formation of a collagen-rich fibrous cap. Glucose utilization and glycolysis control vSMC dedifferentiation, while arginine and tryptophan metabolism influence vSMC phenotypes and vascular calcification. 3. **Macrophage Immunometabolism**: Macrophages exhibit plasticity, transitioning between pro-inflammatory and pro-resolving states. Dysregulated cholesterol metabolism in macrophages leads to foam cell formation and atherosclerosis progression. Glycolysis and oxidative phosphorylation (OXPHOS) in macrophages are critical for inflammation and its resolution. 4. **T Cell Metabolism and Autoimmunity**: T cells, particularly regulatory T (Treg) cells and helper T (Th) cells, play a crucial role in atherogenesis. Metabolic reprogramming in T cells affects their function and fate, with specific nutrients like glucose and amino acids influencing T cell responses in autoimmunity. The review emphasizes the need for precise and carefully considered therapeutic interventions to target these metabolic alterations, considering the potential risks and benefits of metabolic manipulation in atherosclerosis.