The bone-regenerative potentials of the periosteum have been explored as early as the 17th century. Over the past few years, however, much has been discovered in terms of the molecular and cellular mechanisms that control the periosteal contribution to bone regeneration. Lineage tracing analyses and knock-in transgenic mice have helped define the relative contributions of the periosteum and endosteum to bone regeneration. Additional studies have shed light on the critical roles that BMP, FGF, Hedgehog, Notch, PDGF, Wnt, and inflammation signaling have or may have in periosteal-mediated bone regeneration, fostering the path to novel approaches in bone-regenerative therapy. Thus, by examining the role that each pathway has in periosteal-mediated bone regeneration, in this review we analyze the status of the current research on the regenerative potential of the periosteum. The provided analysis aims to inform both clinician-scientists who may have interest in the current studies about the biology of the periosteum as well as dental surgeons who may find this review useful to perform periosteal-harnessing bone-regenerative procedures.