Endothelial cells produce huge proteomes from a relatively small total number of ECs. The ECs’ complex intercellular communication is possible through well-stored, classified, and compartmentalized secretory pathways, intermediated by the secretory vesicles and granules, with the purpose to maintain vascular homeostasis and integrity. Secreted proteins are involved in a myriad of cell communication processes. The local vascular microenvironment dynamically and constantly modifies the ECs’ secretome. We focus on the biological significance of secretome proteins in a healthy vascular microenvironment and under cardiovascular conditions. Vascular ECs crosstalk with other ECs, and other blood cells at a distance, with the circulating hematopoietic stem cells permitting adequate reactions to vascular injury, systemic or local inflammation, and viral or parasitic infections. Here, we overview current secretome biomarkers in vascular diseases, with a focus on their roles in diagnostic, prognostic, and therapeutics. Also, we highlighted some important pathological effects of exosome on cardiovascular disease. This chapter discusses current research directions characterizing vascular pathology conditioned secretomes, their regulation, and therapeutic pursuit. The overall aim of this chapter is to review current literature updates on endothelial secretome roles in endothelial homeostasis and in vascular disorders.