Liver fibrosis is a complex disease affecting millions of people world-wide. It involves the activation of several cell types whose activities are tightly controlled by endogenous mediators. No pharmacotherapy is available for this disease, despite the fact that many experimental drugs are very effective in vitro and the liver is easily accessible for most drugs. Our review provides arguments showing that cell-selectivity is essential for most antifibrotics. Several cell-specific drug carriers targeting the key pathogenic liver cells are discussed with special focus on hepatic stellate cells and fibroblast-like cells. Since endogenous mediators represent a powerful set of tools to modify the pathogenic process, this review focuses on these mediators as therapeutics and the problems and pitfalls associated with the use of such biologicals.