This review strived to provide an unbiased analysis of the current literature in regard to nonsteroidal anti-inflammatory drugs and their effect on bone healing. Overwhelmingly, this review demonstrates that NSAIDs inhibit or delay fracture healing to a greater or lesser degree, depending on the specific drug, mode of administration, administration period and ability to inhibit COX-2. The majority of animal studies and the few human studies that exist support this conclusion. Since it is increasingly clear that the function of COX-2 is critical for bone regeneration, defining the risk-benefit ratio for NSAID use is critical. Patient co-morbid conditions, such as, fracture severity, advanced age, diabetes, and cardiovascular health, will need to be considered when assessing the risk-benefit ratio. Future research is needed to define the role of COX-2 in bone regeneration and whether NSAID therapy will further impair fracture healing or other regenerative processes in the presence of these co-morbid conditions. Research using rodent and rabbit models provides strong evidence that NSAID negatively affect bone healing. Whether this effect is clinically important is controversial in both human and veterinary medicine. Further experimental and clinical trials involving domestic species and veterinary NSAID are needed to guide veterinarians as they decide which, when, atwhat dose, and for how long NSAID should be prescribed after bone injury.