Liver progenitor cells (LPCs) are a promising source of cells to treat liver disease by cell therapy, due to their capability for self-replication and bipotentiality. In order to establish useful culture systems of LPCs and apply them to future clinical therapies, it is necessary to understand their interactions with their microenvironment and especially with the extracellular matrix (ECM). There is considerable evidence from in vivo studies that matrix proteins affect the activation, expansion, migration and differentiation of LPCs, but the information on the role that specific ECMs play in regulating LPCs in vitro is more limited. Nevertheless, current studies suggest that laminin, collagen type III, collagen type IV and hyaluronic acid help to maintain the undifferentiated phenotype of LPCs and promote their proliferation when cultured in media supplemented with growth factors chosen for LPC expansion, whereas collagen type I and fibronectin are generally associated with a differentiated phenotype under the same conditions. Experimental evidence suggests that α6β1 and α5β1 integrins as well as CD44 on the surface of LPCs, and their related downstream signals, are important mediators of interactions between LPCs and the ECM. The interactions of LPCs with the ECM form the focus of this review and the contribution of ECM molecules to strategies for optimizing in vitro LPC cultures for therapeutic applications is discussed.