Efforts to therapeutically stimulate or inhibit vessel growth have been primarily focused on vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 (Flk-1), while little attention has been devoted to the therapeutic potential for angiogenic disorders of placental growth factor (PlGF), a VEGF family member, and its receptor VEGFR-1 (Flt-1). However, recent developments and insights could shift that focus to P1GF and Flt-1. Indeed, PlGF stimulated angiogenesis and collateral growth in ischemic heart and limb with at least a comparable efficiency to VEGF and did not cause side effects associated with VEGF, such as edema or hypotension. An anti-Flt-1 antibody suppressed neovascularization in tumors and ischemic retina, and angiogenesis and inflammatory joint destruction in arthritis. The anti-Flt-1 antibody also reduced atherosclerotic plaque growth and vulnerability, but the atheroprotective effect was not due to reduced plaque neovascularization. The anti-inflammatory effects of the anti-Flt-1 antibody were attributable to a reduced mobilization of bone marrow-derived myeloid progenitors into the peripheral blood, a reduced mobilization/differentiation (and impaired infiltration) of Flt-1-expressing leukocytes into inflamed tissues, and a defective activation of myeloid cells. Thus, PlGF and Flt-1 constitute potential candidates for therapeutic modulation of angiogenesis and inflammation.