This prelude to Engineering of Cell Microenvironment Using Novel focuses on reporting recent advances and trends in the development of functional hydrogel systems to engineer cell microenvironment for various emerging applications, such as biomanipulation, tissue engineering, and regenerative medicine. Typically, hydrogel systems are network of macromolecular polymers crosslinked through physical or covalent bonds. The unique three-dimensional (3D) net structure endows hydrogels with highly absorbent ability and flexible mechanical properties. These characteristic properties of hydrogels offer them with biomimicking properties to natural extracellular matrix (ECM) in vitro, especially useful for biomedical and pharmaceutical applications. In recent years, novel hydrogel systems with extra structural features, functionalities, or properties have gained increasing attentions and exhibited significant impact for biological, biomedical, and pharmaceutical applications. Such state-of-the-art hydrogel systems can be hybrid, nano/microstructure patterned, multifunctional, and responsive. These add-on features of the functional hydrogels enable the precise manipulation of cell biological, physical, mechanical, and electrical microenvironment in vitro, demonstrating to be ideal model systems to direct dynamic tissue regeneration and to study basic cell biological behaviors.