Forskolin (FSK), an activator of adenylate cyclase in many tissues, was investigated to determine its potential for studying cyclic AMP-mediated, physiological events in bone. Tibiae from 14-day chick embryos were cultured in modified Eagle's medium for up to 8 hr, and the cyclic AMP and Ca 2+ efflux responses to parathyroid hormone (PTH) and FSK were observed. FSK caused a concentration-related increase in tissue cyclic AMP, with 10 −6 M FSK producing a cyclic AMP response of similar magnitude to that elicited by 10 −6 M PTH (1–34). However, while 10 −6 M PTH was the maximally-activating PTH concentration, a further elevation was produced by 10 −5 M FSK. Chick embryo tibiae cultured for 8 hr in the presence of PTH exhibited a concentration-related stimulation of Ca 2+ efflux up to 10 −6 M PTH. When this physiological effect was examined in bones cultured in the presence of FSK, a biphasic response to increasing FSK concentrations was found; Ca 2+ efflux was stimulated by 10 −6 M and 3 × 10 −6 M FSK, but not by 10 −7 M or 10 −5 M FSK. In summary, concentrations of FSK, which produced tissue cyclic AMP accumulation similar to that produced by physiologically effective PTH concentrations, also resulted in net Ca 2+ efflux from bone. These results indicate that FSK may be a useful agent for studying the role of cyclic AMP in the response of bone to hormones.