Poor compliance and persistence are among the most significant reasons for failed pharmacotherapy encountered in clinical practice. Consequences of poor compliance range from minor to serious, depending on drug characteristics, disease state, and severity of disease. Compliance and persistence are particular problems for patients with a disorder such as osteoporosis, which remains asymptomatic for long periods. Poor compliance with bisphosphonate therapy for osteoporosis has been associated with a smaller decrease in the rate of bone turnover and smaller improvements in bone mineral density, and may potentially result in a higher risk of fracture and disability. The compliance problem is additive; complex dosing guidelines may contribute to poor compliance with therapy, and the failure to follow these guidelines may result in treatment-related adverse events that further reduce compliance. In the long term, these issues often result in nonpersistence with treatment. In addition to direct consequences for the patient, poor compliance is associated with significant healthcare costs. Studies suggest that less-frequent dosing regimens improve compliance; however, even among patients receiving weekly bisphosphonates, persistence may remain suboptimal. Several strategies are available to improve compliance and persistence with osteoporosis therapies. Good communication between the healthcare provider and the patient--with continuous reinforcement of the importance of treatment--is a key approach to improving persistence. Patients should receive feedback to confirm that their treatment is having an effect, and individualized reminder systems should be recommended to help the patient adhere to the treatment plan. Potentially, every patient is liable to discontinue treatment even after a long period of regular dosing. It should be assumed that every patient receiving therapy for osteoporosis needs regular reinforcement of the importance of continuing therapy.