Bisphosphonates were discovered 40 years ago and remain the market leader in the field of osteoporosis. Bisphosphonates are classified as inhibitors of bone resorption and they act by inhibiting the mevalonate pathway to inhibit protein prenylation with resultant inhibition of osteoclastic activity. There are three ethical bisphosphonates as well as generic alendronate that have been approved for the treatment of osteoporosis in South Africa. These drugs offer a wide range of variations in dose, frequency of administration and method of administration. The wide choice in method of administration may lead to improved individual compliance to treatment protocols. There is strong evidence to support antifracture efficacy at vertebral and hip sites in patients treated for up to three years but long-term data as well as prospective data in osteopenic patients are lacking. Gastrointestinal side-effects are common, but can often be avoided by taking medication in the prescribed fashion. The acute phase response to intravenous administration can be prevented by co-administration of oral paracetamol or ibuprofen. Bisphosphonates can cause bone pain. The Food and Drug Administration (FDA) has accepted evidence that bisphosphonates do not cause atrial fibrillation. Osteonecrosis of the jaw is a rare complication of oral bisphosphonates as used in osteoporosis but may be associated with high dose intravenous treatment in cancer patients. Atypical low energy femur shaft fractures have been associated with long-term usage of the bisphosphonates. A large national observational register-based study reported that these fractures share the same epidemiology and treatment response as classical hip fractures and are best classified as osteoporotic fractures. The cost-effectiveness and treatment options of the bisphosphonates will ensure that they remain significant players in years to come.