The article discusses the use of hydrogels as extracellular matrix (ECM) mimics for three-dimensional (3D) cell culture. It highlights the limitations of traditional two-dimensional (2D) cell culture and the advantages of 3D culture platforms, such as hydrogels, in recapitulating the complex microenvironment that cells experience in vivo. The authors review the properties and challenges of both synthetic and natural hydrogels, emphasizing the need for materials that combine the benefits of both types. They also explore the design criteria for creating bioactive hydrogels that can mimic the ECM's mechanical and biochemical cues, including the presentation of integrin-binding ligands, growth factors, and the ability to control their release over time. The article concludes by discussing the future directions in hydrogel development, including the integration of advanced techniques and the creation of dynamic ECM mimics to better understand cell behavior in vitro.The article discusses the use of hydrogels as extracellular matrix (ECM) mimics for three-dimensional (3D) cell culture. It highlights the limitations of traditional two-dimensional (2D) cell culture and the advantages of 3D culture platforms, such as hydrogels, in recapitulating the complex microenvironment that cells experience in vivo. The authors review the properties and challenges of both synthetic and natural hydrogels, emphasizing the need for materials that combine the benefits of both types. They also explore the design criteria for creating bioactive hydrogels that can mimic the ECM's mechanical and biochemical cues, including the presentation of integrin-binding ligands, growth factors, and the ability to control their release over time. The article concludes by discussing the future directions in hydrogel development, including the integration of advanced techniques and the creation of dynamic ECM mimics to better understand cell behavior in vitro.