Chemokines are a large group of small cytokines known for their chemotactic ability to regulate the recruitment of leukocytes to sites of inflammation. This occurs through the binding of chemokines to their receptors located on the leukocyte that results in cellular changes such as actin rearrangement and cell shape, which allow for the migration of the leukocyte. In addition to regulating leukocyte function, it is now becoming apparent that other nonhematopoetic cells, such as smooth muscle cells and endothelial cells, can also be regulated by chemokines. Studies within the past 10 years has demonstrated the presence of various chemokine receptors on endothelial cells as well as the ability of chemokines to activate these receptors resulting in various cellular responses including migration, proliferation, and cellular activation. The purpose of this review is to highlight the research that has been done to date demonstrating the important role for chemokines in regulating endothelial function during various inflammatory conditions associated with angiogenesis, homeostasis, and leukocyte transmigration. This review will focus specifically on the role of the endothelium in mediating chemokine effects associated with wound healing, atherosclerosis, and autoimmune diseases, conditions where leukocyte recruitment and angiogenesis play a major role. Recent progress in the development and implementation of therapeutics agents against these small molecules, or their receptors, will also be addressed.