Hepatic fibrosis represents the wound-healing response process of the liver to chronic injury, independently from aetiology. Advanced liver fibrosis results in cirrhosis that can lead to liver failure, portal hypertension and hepatocellular carcinoma. Currently, no effective therapies are available for hepatic fibrosis. After the definition of hepatic stellate cells (HSCs) as the main liver extracellular matrix-producing cells in the 1980s, the subsequent decade was dedicated to determine the role of specific cytokines and growth factors. Fibrotic progression of chronic liver diseases can be nowadays considered as a dynamic and highly integrated process of cellular response to chronic liver injury. The present review is dedicated to the novel mechanisms of cellular response to chronic liver injury leading to hepatic myofibroblasts' activation. The understanding of the cellular and molecular pathways regulating their function is crucial to counteract therapeutically the organ dysfunction caused by myofibroblasts' activation.