Liver fibrosis is at the epicenter of clinical hepatology, contributing to most complications of chronic liver disease and often dictating long-term outcome. In the past three decades, there have been tremendous advances in the knowledge of the natural history as well as the genetic and environmental factors that influence the progression of liver fibrosis. Moreover, we have gained deep insight into fibrogenic cell types in the liver, identified several key molecular drivers that trigger fibrogenic responses, and developed improved methods to monitor fibrosis progression and regression. Current efforts are focused on translating our improved understanding of the underlying biological processes to clinical hepatology. The recent achievements in the treatment of viral hepatitis have led the field to start refocusing on the next important challenges in hepatology. With the key role of fibrosis in clinical hepatology, increased appreciation of the concept of fibrosis reversibility, and recent Food and Drug Administration approval of antifibrotics in other organs, there is a revived enthusiasm about antifibrotic treatment in the field, which has led to the first large-scale antifibrotic trials. Ironically, the recent successes of new antivirals in hepatitis C may result in a large number of patients that are cured of the underlying disease, but not the accompanying fibrosis—further promoting interest in antifibrotic treatments. Moreover, the shift of the patient spectrum from viral hepatitis to increasing numbers of patients with nonalcoholic steatohepatitis (NASH) and the unchanged high number of patients with alcoholic liver disease (ALD) will require the basic and clinical research communities to better understand how fibrosis arises and how it can be treated in these settings.