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The proliferative response of cholangiocytes during cholestasis is regulated by the complex interaction of several factors, including gastrointestinal hormones, neuroendocrine hormones and autocrine or paracrine signalling mechanisms. Activation of biliary proliferation (ductular reaction) is thought to have a key role in the initiation and progression of liver fibrosis. The first part of this review provides an overview of the primary functions of cholangiocytes in terms of secretin-stimulated bicarbonate secretion \u2013 a functional index of cholangiocyte growth. In the second section, we explore the important regulators, both inhibitory and stimulatory, that regulate the cholangiocyte proliferative response during cholestasis. We discuss the role of proliferating cholangiocytes in the induction of fibrosis either directly via epithelial mesenchymal transition or indirectly via the activation of other liver cell types. 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