The successful treatment of patients at increased risk for fracture requires proper diagnosis and the development of a treatment plan that permits the patient to take medications in accordance with dosing guidelines and on the correct schedule. Data indicate that patients with osteoporosis who have good long-term medication compliance experience substantially lower risk of fracture. Persistence with therapy also correlates with better bone mineral density and improved suppression of bone turnover markers. Although bisphosphonates are the most potent currently approved antiresorptive agents, they have special dosing issues that can have a negative impact on long-term persistence. The inconvenience and complexity of some dosing requirements; the potential for adverse effects, especially when dosing recommendations are not followed; and very low absorption rates—even under ideal conditions—all contribute to poor outcomes. Extension of the dosing interval from a once-daily to a once-weekly regimen is associated with comparable efficacy, theoretically may improve gastrointestinal safety, and is associated with substantial improvement in persistence with therapy. However, compliance with weekly regimens remains suboptimal. Monthly dosing of ibandronate, a bisphosphonate, was recently approved by the US Food and Drug Administration (FDA). Although extending the dosing interval may improve compliance and persistence with bisphosphonate therapy, it is important to recognize that missed doses or improper dosing may have greater consequences with extended dosing intervals. This article highlights the importance of educating patients about their diagnosis and long-term treatment plan, including the importance of persistence with therapy and compliance with dosing recommendations.