A new era in osteoporosis management began with the recent approval of parathyroid hormone (PTH) for postmenopausal and idiopathic osteoporosis treatment. Intermittent PTH dramatically increases spine bone mineral density and significantly reduces fragility fractures. However, the skeletal response to PTH varies greatly and there are few large scale, randomized, placebo-controlled trials in conditions such as glucocorticoid-induced osteoporosis. Moreover, the mechanisms of PTH action are complex, involving multiple pathways linked to common signaling peptides regulating osteoblast gene transcription. In addition, important interactions between osteoclasts and osteoblasts are activated by PTH. This review presents recent findings on PTH signaling in bone and discusses how they could be used to design randomized trials and establish clinical practice guidelines for this novel anabolic peptide.