Fibrosis is due to excess in extracellular matrix (ECM) deposition over reabsorption resulting in tissue distortion eventually leading to organ dysfunction, organ failure, and death. Central to any fibrotic response, myofibroblasts are contractile cells with high ECM synthetic capacity. The inflammatory response triggered by tissue damage and aiming at tissue repair is characterized by an array of factors and cells, which result in fibrosis with sustained and relentless myofibroblast recruitment and activation. In addition, macrophages and receptors belonging to the innate immune system are fundamental in initiating and maintaining myofibroblast activation. In some circumstances, cells of the adaptive immune system, namely, T and B cells, are thought to participate to fibrosis development. In this respect it is noteworthy that IL-4 and IL-13 produced by Th2 cells, often expanded in IgG4-related disease, provide direct pro-fibrotic stimulation. The basic mechanisms linking innate and adaptive immune responses and fibrosis are reviewed herein, with a particular focus on their participation in fibro-inflammatory disorders.