The primary goal of treatment for post-menopausal osteoporosis (PMO) is reduction in fracture risk. Therefore, clinicians must recommend therapies that are safe and have proven anti-fracture efficacy. Bisphosphonates have long been established as first-line therapy for osteoporosis and several of these drugs significantly reduce osteoporotic fracture risk. However, choosing among different bisphosphonates can represent a difficult clinical decision. This review outlines the pharmacology of various bisphosphonates, discusses how their pharmacological characteristics affect their efficacy, and summarizes clinical safety and efficacy data. Clinical trial data and the opinions of expert bodies suggest that alendronate, risedronate, ibandronate and zoledronic acid all provide fracture protection for patients with PMO. However, there are differences among these agents. For example, all four agents have demonstrated efficacy in preventing vertebral fractures, but only zoledronic acid and risedronate significantly reduce non-vertebral fracture risk in pivotal trials. Moreover, reduction in hip fracture risk has only been established for alendronate, risedronate and zoledronic acid. Current data suggest that ibandronate and zoledronic acid have the most persistent antifracture effect. Bisphosphonates have been associated with a number of side effects, the evidence for which is summarized in this review. The most pertinent of these when choosing a bisphosphonate for a particular patient are the well-documented associations between gastrointestinal adverse events and oral administration, and between acute phase reactions and intravenous administration. Ultimately, selection of a specific bisphosphonate for treatment of PMO should be based on efficacy, risk profile, cost-effectiveness and patient preference.