Anti-resorptives that prevent osteoclasts from resorbing bone are the mainstay of treatment for osteoporosis, while parathyroid hormone is the only agent available that stimulates osteoblasts to form bone. Advances in knowledge about metabolic pathways in bone cell biology have identified specific points of intervention whereby formation and function of osteoclasts and osteoblasts can be inhibited or stimulated. The next generation of therapies for osteoporosis may include molecules that antagonize integrin or inhibit Src tyrosine kinase, vacuolar H+-ATPase, chloride channel or cathepsin K, thus preventing osteoclasts from attaching to bone, form a ruffled border, acidify resorption lacunae or digest organic bone matrix. At least some of these may form a novel class of anti-resorptives capable of inhibiting bone resorption without being coupled to inhibition of bone formation. Human and mouse genetics studies demonstrating the pivotal role of the Wnt signaling pathway in bone metabolism have led to the development of strategies to disrupt Wnt signaling in order to increase bone formation. Selective androgen receptor modulators that produce an anabolic effect on muscle and bone without undesirable androgenic side effects can potentially be used to treat osteoporosis, aged-related frailty, muscle wasting disorders and glucocorticoid-induced osteoporosis. Studies involving these molecules are still in either preclinical or early investigational stage, without fracture data. Nonetheless, preliminary results hold the promise that at least some of these new therapies may develop into effective means of treating and preventing osteoporosis. Any new therapy for osteoporosis must take into consideration its safety, efficacy, affordability and specificity of action.