Bisphosphonates, pyrophosphate analogs which potently inhibit osteoclastic bone resorption, are now firmly established as first-line therapy for osteoporosis. Several bisphosphonates of varying antiresorptive potency are either in clinical use or well advanced in clinical trials. Alendronate and risedronate are agents of choice at present because data from randomized controlled trials demonstrate that each of these nitrogen (N)-containing-bisphosphonates reduces the incidence of vertebral and nonvertebral fractures by about 50%, whereas evidence for antifracture efficacy is limited to the vertebral site currently for other bisphosphonates such as etidronate and ibandronate. There have not been direct studies comparing the antifracture efficacy of alendronate with that of risedronate. Intermittent administration of bisphosphonates is now a well established clinical practice, and the potent bisphosphonate zoledronate produces suppression of bone resorption for at least 12 months after a single intravenous dose. Future research will better define how to optimally administer these agents to maximize efficacy and patient compliance. The place in osteoporosis therapeutics of combining bisphosphonate therapy with agents that primarily stimulate bone formation, such as parathyroid hormone, remains to be defined.