Placental growth factor (PlGF) is a member of the vascular endothelial growth factor (VEGF) family that also comprises VEGF-A (VEGF), VEGF-B, VEGF-C, and VEGF-D. Unlike VEGF, PlGF is dispensable for development and health but has diverse nonredundant roles in tissue ischemia, malignancy, inflammation, and multiple other diseases. Genetic and pharmacological gain-of-function and loss-of-function studies have identified molecular mechanisms of this multitasking cytokine and characterized the therapeutic potential of delivering or blocking PlGF for various disorders.