Recent studies have challenged the conventional hypothesis that inflammation is the major player in the fibrosis cascade. Emerging evidence points to a critical role for interactions between tissue-resident and infiltrating, non-resident cells, in mediating fibrotic responses. Improved understanding of the biology of extracellular matrix (ECM) remodeling and the pathways that regulate assembly of the ECM and its interactions with growth factors/cytokines have led to the identification of new and attractive therapeutic targets. These include molecules that regulate fibrocytic cell infiltration, epithelial and myofibroblast differentiation, ECM synthesis and degradation. However, it is imperative that these new therapies be timed and compartmentalized to target the tissue of interest, as the dynamics of cellular differentiation and ECM remodeling may be different between organ systems. This review will summarize the current understanding of the mechanisms involved in the development of fibrosis, based on recent in vitro and in vivo studies, and comment on novel molecular pathways for drug discovery.