Prostaglandins are locally secreted, rapidly metabolized, biologically active fatty acids first identified in the prostate. The role of prostaglandins in the inflammatory response has been widely studied. However, some prostaglandins, particularly those of the E series (PGEs), can suppress inflammation, making it difficult to understand the local events and their sequence. This bimodal potential of the PGEs has been poorly understood in skeletal biology, causing the initial report of PGEs as mediators of bone resorption to persist for more than two decades, despite ample evidence to the contrary. This resulted in part from the power of any initial report to overrule subsequent conflicting views and in part on the exclusive reliance on in vitro data to explain in vivo phenomena. Over a decade ago, the potential of PGEs as authentic anabolic skeletal agents was demonstrated convincingly in vivo by both systemic and local delivery. The potential clinical applications of the PGEs in skeletal biology have not yet been developed. Our purpose is to review the reasons for the delayed discovery of the true skeletal effects of the PGEs and to describe applications for this technology. With the development of appropriate delivery systems, one can anticipate widespread clinical applications of the PGEs to accelerate skeletal repair, and to treat skeletal pathologies and trauma.