The developmental Hedgehog (Hh) protein family is known to be pivotal in many embryonic patterning events and the number of processes in which Hh plays an essential role is expanding persistently. Recently, it has become clear that the Hh pathway is not only active in the developing embryo but also in the adult organism. For example, Hh has been suggested to salvage ischemia-induced tissue damage although endogenous Hh might be deleterious during the early phase of myocardial ischemia–reperfusion. The current review provides an overview of the history of Hh biology and discusses some novel insights on Hh cell biology. Hh function in pathophysiology as well as recent findings concerning Hh signaling in ischemia models, especially in light of cardiovascular disease, is discussed in more detail and future perspectives are proposed.