As extracellular matrices (ECM) closely interact with cells in living tissues and, through this, influence essentially any aspect of life engineering of ECM currently receives a lot of attention in the advent of regenerative therapies. Artificial matrices based on biopolymers isolated from nature were successfully utilized to prepare various types of cell scaffolds to enhance the integration and performance of engineered tissues. Beyond that, translation of progress in matrix and cell biology into new concepts of materials science permits to further refine the functional characteristics of such reconstituted matrices to direct tissue regeneration processes. The review emphasizes research to modulate the functionality of ECM biopolymers through their combination with synthetic polymeric materials. Two examples referring to our own studies concern (1) the control of vasculogenesis by adjusting the availability of surface bound fibronectin for cell-driven reorganization and; (2) the imitation of the bone marrow niche with respect to the cultural amplification of hematopoietic progenitor cells using collagen I-based assemblies. As a perspective we briefly discuss the design of biohybrid ECM mimics where synthetic and natural polymers are combined on the molecular scale for future use as morphogenetic templates in in vivo tissue engineering applications.