Arachidonic acid (AA) and its metabolites (eicosanoids) represent powerful mediators, used by organisms to induce and suppress inflammation as a part of the innate response to disturbances. Several cell types participate in the synthesis and release of AA metabolites, while many cell types represent the targets for eicosanoid action. Endothelial cells (EC), forming a semi-permeable barrier between the interior space of blood vessels and underlying tissues, are of particular importance for the development of inflammation, since endothelium controls such diverse processes as vascular tone, homeostasis, adhesion of platelets and leukocytes to the vascular wall, and permeability of the vascular wall for cells and fluids. Proliferation and migration of endothelial cells contribute significantly to new vessel development (angiogenesis). This review discusses endothelial-specific synthesis and action of arachidonic acid derivatives with a particular focus on the mechanisms of signal transduction and associated intracellular protein targets.