Endothelial cells, which line the innermost layer of blood vessels, play crucial roles in hemostasis, arterial tone, wound healing, and tissue oxygen and nutrient supply. With age, these cells become senescent, characterized by reduced regeneration capacity, inflammation, and abnormal secretory profiles. Endothelial senescence is an early feature of arterial aging and contributes to various age-related diseases. Microvascular endothelial cells exhibit greater heterogeneity compared to those in arteries and veins, leading to declined capillary density, reduced angiogenic potential, decreased blood flow, impaired barrier properties, and hypoperfusion in a tissue or organ-dependent manner. The mechanisms underlying macro- and micro-vascular endothelial senescence vary across different pathophysiological conditions, offering specific targets for therapeutic development of senolytic drugs. Endothelial cells undergo cellular senescence, a state of irreversible growth arrest characterized by enlarged cell size, elevated SA-β-gal activity, telomere-associated foci, and increased expression of cyclin-dependent kinase inhibitors. Senescent cells accumulate with age, contributing to tissue degeneration and age-related diseases. Systemic clearance of senescent cells delays aging and extends lifespan. Senotherapy, targeting cellular senescence, is a promising strategy for preventing and treating age-related diseases. The microvasculature, including arterioles, capillaries, and venules, plays a vital role in meeting the oxygen and nutrient requirements of cells and tissues. Aging leads to microvascular dysfunction, characterized by endothelial dysfunction, reduced NO production, increased ROS levels, and low-grade inflammation. Obesity and diabetes mellitus are associated with microvascular dysfunction, leading to structural and functional changes in the coronary vasculature. COVID-19 also causes microvascular endothelial cell damage, contributing to sepsis and death. Endothelial cells differentiate from angioblasts and exhibit morphological and functional heterogeneity. They express angiogenic growth factor receptors and store von Willebrand factor. The microvasculature of different organs displays specialized properties. Brain microvascular endothelial cells (BMECs) form the blood-brain barrier (BBB), which is crucial for neurogenesis and cognitive function. Aging and senescence in BMECs lead to BBB dysfunction and cognitive decline. Heart failure (HF) is a prevalent cardiovascular disease, and endothelial cells play a significant role in cardiac health. Senescent endothelial cells contribute to microvascular dysfunction and cardiac remodeling in failing hearts. Senescent endothelial cells accumulate in the vascular bed, leading to increased SASP expression and vascular rarefaction. Atherosclerosis, a chronic inflammatory disease, is influenced by cellular senescence. Senescent endothelial cells reduce NO production and increase vasoconstrictive factors, contributing to hypertension. The BBB disruption in aged subjects is a hallmark of cerebrovascular diseases and cognitive decline. Senescent endothelial cells in the heart contribute to diEndothelial cells, which line the innermost layer of blood vessels, play crucial roles in hemostasis, arterial tone, wound healing, and tissue oxygen and nutrient supply. With age, these cells become senescent, characterized by reduced regeneration capacity, inflammation, and abnormal secretory profiles. Endothelial senescence is an early feature of arterial aging and contributes to various age-related diseases. Microvascular endothelial cells exhibit greater heterogeneity compared to those in arteries and veins, leading to declined capillary density, reduced angiogenic potential, decreased blood flow, impaired barrier properties, and hypoperfusion in a tissue or organ-dependent manner. The mechanisms underlying macro- and micro-vascular endothelial senescence vary across different pathophysiological conditions, offering specific targets for therapeutic development of senolytic drugs. Endothelial cells undergo cellular senescence, a state of irreversible growth arrest characterized by enlarged cell size, elevated SA-β-gal activity, telomere-associated foci, and increased expression of cyclin-dependent kinase inhibitors. Senescent cells accumulate with age, contributing to tissue degeneration and age-related diseases. Systemic clearance of senescent cells delays aging and extends lifespan. Senotherapy, targeting cellular senescence, is a promising strategy for preventing and treating age-related diseases. The microvasculature, including arterioles, capillaries, and venules, plays a vital role in meeting the oxygen and nutrient requirements of cells and tissues. Aging leads to microvascular dysfunction, characterized by endothelial dysfunction, reduced NO production, increased ROS levels, and low-grade inflammation. Obesity and diabetes mellitus are associated with microvascular dysfunction, leading to structural and functional changes in the coronary vasculature. COVID-19 also causes microvascular endothelial cell damage, contributing to sepsis and death. Endothelial cells differentiate from angioblasts and exhibit morphological and functional heterogeneity. They express angiogenic growth factor receptors and store von Willebrand factor. The microvasculature of different organs displays specialized properties. Brain microvascular endothelial cells (BMECs) form the blood-brain barrier (BBB), which is crucial for neurogenesis and cognitive function. Aging and senescence in BMECs lead to BBB dysfunction and cognitive decline. Heart failure (HF) is a prevalent cardiovascular disease, and endothelial cells play a significant role in cardiac health. Senescent endothelial cells contribute to microvascular dysfunction and cardiac remodeling in failing hearts. Senescent endothelial cells accumulate in the vascular bed, leading to increased SASP expression and vascular rarefaction. Atherosclerosis, a chronic inflammatory disease, is influenced by cellular senescence. Senescent endothelial cells reduce NO production and increase vasoconstrictive factors, contributing to hypertension. The BBB disruption in aged subjects is a hallmark of cerebrovascular diseases and cognitive decline. Senescent endothelial cells in the heart contribute to di