Chronic liver disease prevalence is increasing globally. Iterative liver damage, secondary to any cause of liver injury, results in progressive fibrosis, disrupted hepatic architecture, and aberrant regeneration, which are defining characteristics of liver cirrhosis. Liver transplantation is an effective treatment for end-stage liver disease; however, demand greatly outweighs donor organ supply, and in many parts of the world liver transplantation is unavailable. Hence, effective antifibrotic therapies are urgently required. In the past decade, rapid progress has been made in our understanding of the pathophysiology of liver fibrosis and a large number of potential cellular and molecular antifibrotic targets have been identified. This has led to numerous clinical trials of antifibrotic agents in patients with chronic liver disease. However, none of these have resulted in a robust and reproducible effect on fibrosis. It is therefore imperative that the ongoing translational challenges are addressed, to convert scientific discoveries into potent antifibrotics and enable bridging of the translational gap between putative therapeutic targets and effective treatments for patients with chronic liver disease.