Reactive oxygen species, such as superoxide anion (O2(-)) and H2O2, cause oxidative stress in endothelial cells, a condition implicated in the pathogenesis of many cardiovascular and pulmonary diseases. Antioxidant enzymes, superoxide dismutases (SOD, converting superoxide anion into H2O2) and catalase (converting H2O2 into water), are candidate drugs for augmentation of antioxidant defenses in endothelium. However, SOD and catalase undergo fast elimination from the bloodstream, which compromises delivery and permits rather modest, if any, protection against vascular oxidative stress. Coupling of polyethylene glycol (PEG) to the enzymes and encapsulating them in liposomes increases their bioavailability and enhances their protective effect. Chemical modifications and genetic manipulations of SOD and catalase have been proposed in order to provide more effective delivery to endothelium. For example, chimeric protein constructs consisting of SOD and heparin-binding peptides have an affinity for charged components of the endothelial glycocalix. However, the problem of developing a more effective and precise delivery of the drugs to endothelial cells persists. Endothelial surface antigens may be employed to provide targeting and subcellular addressing of drugs (vascular immunotargeting strategy). Thus, SOD and catalase conjugated to antibodies directed against the constitutively expressed endothelial antigens, angiotensin-converting enzyme (ACE) and adhesion molecules (ICAM-1 or PECAM-1), bind to endothelium in intact animals after intravascular administration, accumulate in the pulmonary vasculature, enter endothelial cells and augment their antioxidant defenses. Such immunotargeting strategies may provide secondary therapeutic benefits by inhibiting the function of target antigens. For example, blocking of ICAM-1 and PECAM-1 by carrier antibodies may attenuate inflammation and leukocyte-mediated vascular damage. Additional studies in animal models of vascular oxidative stress are necessary in order to more fully characterize potential therapeutic effects and limitations of targeting of antioxidant enzymes to endothelial cells.