Defective ribosome biogenesis (RiBi) underlies a group of clinically diverse human diseases collectively known as the ribosomopathies, core manifestations of which include cytopenias and developmental abnormalities that are believed to stem primarily from an inability to synthesize adequate numbers of ribosomes and concomitant activation of p53. The importance of a correctly functioning RiBi machinery for maintaining tissue homeostasis is illustrated by the observation that, despite having a paucity of certain cell types in early life, ribosomopathy patients have an increased risk for developing cancer later in life. This suggests that hypoproliferative states trigger adaptive responses that can, over time, become maladaptive and inadvertently drive unchecked hyperproliferation and predispose to cancer. Here we describe an experimentally induced ribosomopathy in the mouse and show that a normal level of hepatic ribosomal protein S6 (Rps6) is required for proper bile duct development and preservation of hepatocyte viability and that its insufficiency later promotes overgrowth and predisposes to liver cancer which is accelerated in the absence of the tumor-suppressor PTEN. We also show that the overexpression of c-Myc in the liver ameliorates, while expression of a mutant hyperstable form of p53 partially recapitulates specific aspects of the hepatopathies induced by Rps6 deletion. Surprisingly, co-deletion of p53 in the Rps6-deficient background fails to restore biliary development or significantly improve hepatic function. This study not only reveals a previously unappreciated dependence of the developing liver on adequate levels of Rps6 and exquisitely controlled p53 signaling, but suggests that the increased cancer risk in ribosomopathy patients may, in part, stem from an inability to preserve normal tissue homeostasis in the face of chronic injury and regeneration. Author summary: Ribosomopathies are a group of human diseases caused by mutations in genes that are required for ribosome biogenesis (RiBi), the process by which ribosomes, the molecular machines that synthesize all of the proteins in our bodies, are made. Here we show that mice that lack sufficient levels of one such gene, ribosomal protein S6 (Rps6) as the liver develops, fail to develop primary bile ducts resulting in disease reminiscent of North American Indian childhood cirrhosis (NAIC), a liver-specific ribosomopathy caused by mutations in a different RiBi gene, UTP4. Hepatocytes in Rps6-deficient livers also die resulting in small, abnormal livers that are forced to regenerate and predisposed to develop cancer. To determine the contribution of p53, a primary effector of the anti-proliferative response that is often triggered by dysfunctional RiBi to the liver disease caused by Rps6-deficiency, we find that forced activation of p53 inhibits bile duct development, but that the disease in Rps6-deficient livers is not solely p53-dependent. This study reveals a previously unappreciated vulnerability of the liver to defective RiBi or inappropriate activation of p53 and implicates both as possible drivers of a subset of congenital biliary or hepatic insufficiency syndromes for which there is currently no known etiology. [ABSTRACT FROM AUTHOR]