Chemokines are a class of small chemotactic molecules with cytokine-like functions, which are well known to orchestrate inflammatory responses within different organs. Overall, more than 50 ligands and 19 receptors belong to the network. In recent years, accumulating functional and genetic evidence suggests that chemokines play a critical role in acute and chronic liver diseases, mediating the infiltration of immune cells (monocytes, T-cells) into the injured liver along a concentration gradient. However, chemokines can also directly affect the biology of liver resident cells, such as hepatic stellate cells and hepatocytes during inflammatory and fibrogenic tissue responses. Although the chemokine system has long been considered highly redundant, studies in knockout animals have convincingly demonstrated that single chemokines and chemokine receptors strongly affect the phenotype of toxic and inflammatory liver disease in vivo. However, depending on the model, these effects can be harmful (proinflammatory, profibrogenic) or beneficial (antifibrotic). This aspect of chemokine biology must be understood before these molecules and their receptors are targeted for therapeutic purposes. Here, we summarize current knowledge on the genetic and functional importance of the chemokine network in injury and highlight their potential for intervening in the inflammation and fibrosis that drives liver disease progression.