As human somatic cells age, they stop replicating and enter an irreversible state of growth arrest known as replicative senescence. Senescent cells are viable, metabolically active, and display altered gene and protein expression compared to proliferating cells. Endothelial cells, both in vitro and in vivo, are known to undergo senescence. As endothelial cells are a critical component of the vasculature, senescence of these cells can have a significant impact of vascular integrity, function, and overall homeostasis. This review will summarize recent work to understand the molecular mechanisms of endothelial cell senescence and the resulting alterations in gene/protein expression in these cells. Endothelial cell senescence will then be discussed in the context of disease development with a focus on atherosclerosis, an important age-associated disease of the vasculature.