The evaluation of molecular pathways has revealed various novel insights into rheumatoid arthritis pathophysiology during the past year. In addition, there is an increasing tendency toward analysis not merely of a single mechanism but rather of data addressing a substantial part of the cascade of events leading to cellular activation. Because synovial fibroblasts are key cells involved in joint destruction, this review outlines the events that trigger or inhibit the crucial pathways leading to their aggressive behavior. Major topics include cellular and humoral interactions (frequently modulated by cytokines), intracellular signaling and upregulation of gene transcription, and the deleterious effects on articular homeostasis.