Nitric oxide is a small free radical generated by a family of enzymes, the nitric oxide synthases (NOSs). In a series of experiments performed over the last 15 years, we showed that nitric oxide is induced by all 3 isoforms of NOS during tendon healing and that it plays a crucial beneficial role in restoring tendon function. In normal tendons, very little NOS activity was found, whereas in injured rat and human tendons, NOS activity was expressed in healing fibroblasts in a temporal fashion. In healing rat Achilles tendon fibroblasts, the first isoform to be expressed was endothelial NOS, followed by inducible NOS and then brain or neuronal NOS. Systemic inhibition of NOS activity decreased the cross-sectional area and mechanical properties of the healing rodent Achilles tendons. The addition of nitric oxide via nitric oxide-flurbiprofen enhanced rat Achilles tendon healing. The addition of nitric oxide to cultured human tendon cells via chemical means and via adenoviral transfection enhanced collagen synthesis, suggesting that one mechanism for the beneficial effect of nitric oxide on tendon healing might be via matrix synthesis. Most recently, 3 randomized, double-blind clinical trials evaluated the efficacy of nitric oxide donation via a patch in the management of the tendinopathy. In all 3 clinical trials, there was a significant positive beneficial effect of nitric oxide donation to the clinical symptoms and function of patients with Achilles tendinopathy, tennis elbow, and supraspinatus tendinitis.