A fter alendronate was approved for the treatment of postmenopausal osteoporosis, expectations rose that new therapies would be developed to cure this debilitating disease. Public and private collaborations pushed the envelope to discover ''druggable'' targets in the skeletal remodeling unit. Initially, those efforts focused on the bone-resorbing osteoclast and ultimately led to the approval of three bisphosphonates that differed not in their mode of action but rather in their frequency of administration. In contrast, the development and subsequent approval of teriparatide paved the way for anabolic therapies that ''turned on'' osteoblasts. In JBMR this month, proof of concept is illustrated for two novel targets in the skeletal milieu, a protease secreted by osteoclasts and a peptide product of the osteocyte. As Einstein noted, the future of osteoporosis medicine is coming soon enough. (1,2) Antiresorptive therapies aimed at the osteoclast have a long and relatively successful history. Estrogen was used to prevent bone loss more than a half a century ago. Remarkably, recent studies have confirmed both its antifracture efficacy and its capacity to prevent bone loss. (3) Estrogens block bone resorption by inhibiting cytokine differentiation of osteoclasts through the RANKL pathway. (4) However, nonskeletal side effects have limited estrogen's utility for the long-term treatment of osteoporosis. Calcitonin was approved for the treatment of osteoporosis in the 1980s. Although osteoclasts express a surface receptor for calcitonin, the antiresorptive effects of nasal or subcutaneous calcitonin were much less pronounced than those of estrogen. In 1995, alendronate was introduced, and the bisphosphonates rapidly became the drugs of choice for the treatment of osteoporosis in part because of their ease of administration and their relatively strong efficacy. This class of agents acts by diffusing into the osteoclast from the skeletal matrix and inhibiting key enzymes in the HMG CoA reductase pathway. Bisphosphonates also can induce osteoclast apoptosis. Very recently, reports of subtrochanteric fractures and the rare occurrence of osteonecrosis of the jaw have spurred investigators to consider other targets in the osteoclast. (5) Odanacatib is a cathepsin K inhibitor currently in phase III trials. Its mode of action is through inhibition of the enzyme cathepsin K (CatK), an abundant cysteine protease produced by osteoclasts and critical for collagenolytic activity. Because CatK is