Osteoporosis is the most common metabolic bone disease (>70 million cases worldwide) and an increasing cause of morbidity and mortality throughout the world. Over the past 10 yr, the understanding of bone physiology and remodeling and the pathophysiology of osteoporosis expanded dramatically. Paralleling these discoveries has been the development of new drugs for the management of osteoporosis with demonstrated efficacy in improving bone mineral density (BMD) and reducing fracture risk. Despite the availability of several Food and Drug Administration-approved agents with demonstrated efficacy and safety, osteoporosis remains a significant clinical problem. Many patients cannot take or tolerate currently available the rapies, and some patients do not adequately respond to treatment. Additionally, no existing therapy can completely eliminate fracture risk. Therefore, research continues to seek more effective and better-tolerated agents. In addition to agents that target unique aspects of bone resorption and bone formation, there are also drugs nearing approaval that that target multiple areas of the bone remodeling cycle and utilize unique dosage forms potentially maximizing efficacy, safety, and adherence. This article reviews bone remodeling, the pathophysiology of osteoporosis, and drug development in osteoporosis. Select agents with novel mechanisms of action or innovative dosing that are in or nearing human clinical trials are discussed, including cathepsin K inhibitors, nitrosylated nonsteroidal anti-inflammatory drugs (NO-NSAIDs), receptor activator of nuclear factor (NF)-KB ligand (RANKL) inhibitor (AMG 162), recombinant complex of insulin-like growth factor-I and insulin-like growth factor binding protein-3 (SomatoKine®), αvβ3-integrin receptor antagonists, and prote in tyrosine kinase Src inhibitors.