Bile duct cells play an important role in maintaining, modifying and augmenting bile flow. It is well established that cyclic AMP (cAMP) is an important second messenger for secretion in these cells, but less is known about cytosolic Ca2+ (Ca-i(2+)). Here we review evidence that ATP and acetylcholine (ACh) an, Ca-i(2+) agonists for bile duct cells, and that these agonists increase Ca-i(2+) through inositol 1,4,5-trisphosphate (InsP(3)). We also review data suggesting that hepatocytes have the ability to secrete ATP, so that they may serve as a paracrine source for this signaling molecule in vivo. Finally, we compare the effects of cAMP and Ca-i(2+) on secretion, both in isolated bile duct units and isolated hepatocyte couplets. Implications and future directions for studying the role of Ca-i(2+) in bile ductular secretion are discussed.