No other member of the VEGF (vascular endothelial growth factor) family has been as mysterious as VEGF-B. Notwithstanding its name, VEGF-B can hardly be regarded as a growth factor because growth occurs fairly normally in Vegf-b deficient mice. Moreover, VEGF-B is barely angiogenic under most conditions, although it was expected to be an angiogenic factor for a long time. Under certain conditions, VEGF-B has been shown to be involved in blood vessel growth. Under other conditions, however, VEGF-B can act to inhibit tumor growth and angiogenesis. Given these contradictory findings, the biological function of VEGF-B appears enigmatic. In this review, we summarize recent advances in VEGF-B biology and discuss its multifaceted roles, the underlying mechanisms, and the potential therapeutic implications.