Vascular endothelial growth factor (VEGF) plays a pivotal role in the development of diabetic macular edema (DME), the leading cause of vision loss among working-aged individuals. A decade of clinical trials demonstrated that drugs that bind soluble VEGF restore the integrity of the blood-retinal barrier, resolve macular edema, and improve vision in most patients with DME. Four drugs (pegaptanib, ranibizumab, bevacizumab, and aflibercept) effectively treat DME when administered by intravitreal injections. Only ranibizumab has received U.S. Food and Drug Administration (FDA) approval for DME, but bevacizumab is commonly used off-label, and an FDA application for aflibercept is pending. Effective treatment requires repeated injections, although recent data suggest that the treatment burden diminishes after 1 year. Intravitreal therapy is generally safe, although the incidence of systemic thromboembolic events varies among trials.