The mode of action of forskolin is of clinical and scientific interest since forskolin has been shown to have potentially therapeutic bone anti-resorptive and anti-hypertensive properties. Forskolin is thought to inhibit the bone resorptive activity of osteoclasts by elevating cytosolic cAMP and to mimic as well as augment the anti-resorptive effect of calcitonin (CT). Other studies have found that forskolin has a dose-dependent dual effect in mouse calavaria, stimulating bone resorption at low doses and having an inhibitory effect at high doses. However, the acute effect of forskolin on osteoclast functional modality has never been studied. The present investigation examined the effect of low (1 mM) and high doses (10 mM) of forskolin on superoxide anion (O2-) generation in isolated bone-resorbing rat osteoclasts. Forskolin was found to have a bimodal cAMP-independent effect on O2- generation, being stimulatory at a low dose and having an inhibitory effect at a higher dose. These findings also suggest that CT-induced inhibition of O2- generation in the osteoclasts is likely to be mediated by cAMP-independent pathways, perhaps involving [Ca2+]i modulation.