Advancing Synthetic Hydrogels through Nature-Inspired Materials Chemistry Synthetic extracellular matrix (ECM) mimics that can recapitulate the complex biochemical and mechanical nature of native tissues are essential for advanced models of development and disease. Biomedical research has relied on animal-derived biomaterials, which hinder translational potential and complicate biological insights. Natural hydrogels have been effective cell culture tools, but advances in materials chemistry and fabrication techniques now offer promising xenogenic-free ECM substitutes for organotypic models and microphysiological systems. However, synthetic matrices must approximate the structural sophistication, biochemical complexity, and dynamic functionality of native tissues. This review summarizes key properties of the native ECM and discusses recent approaches to systematically decouple and tune these properties in synthetic matrices. The importance of dynamic ECM mechanics, such as viscoelasticity and matrix plasticity, is emphasized, particularly in the context of organoid and engineered tissue matrices. Emerging design strategies to mimic these dynamic mechanical properties are reviewed, such as multi-network hydrogels, supramolecular chemistry, and hydrogels assembled from biological monomers. The native ECM provides crucial biochemical and biophysical instruction to resident cells, directing tissue morphogenesis, maturation, and homeostasis. Cells sense ECM mechanics through traction forces and mechanoreceptors, activating mechanosensitive pathways that regulate gene and protein expression. ECM mechanics influence inter/intracellular tension, governing tissue geometry, polarization, and spatial organization. Over longer time scales, these signaling networks impact physiological outcomes like regeneration and pathological outcomes like cancer progression. Synthetic hydrogels mimic the highly hydrated nature of native tissues, composed of cell-laden hydrogels that replicate the biochemical and mechanical properties of native tissues. These natural biopolymers have intricate hierarchical structures and complex chemical compositions, contributing to the dynamic mechanical nature of native tissues. The mechanics of native tissues are characterized by complex viscoelastic behavior, dependent on time and mechanical loading rate. Viscoelastic materials show both an instantaneous elastic response and time-dependent energy dissipation. Viscoelasticity significantly impacts cell- and tissue-level behavior, such as stem cell fate, neural maturation, immune cell specification, and vascular morphogenesis, as well as pathological processes like cancer progression. The inherent chemical complexity of biological polymers results in a poorly defined matrix, necessitating synthetic matrices that can recapitulate the dynamic, time-dependent mechanics of biological ECMs. Traditional synthetic hydrogel systems feature linearly elastic networks of high molecular-weight polymers, allowing high engineering control but not distributing cell-generated stresses physiologically. Decellularized animal-secreted ECMs mimic tissue mechanical responses but restrict experimental control and reproducibility. Recent progress in biomimetic materials chemistry and biofabrication design has narrowed this gap. Viscoelastic materials can more realistically capture how exogenous forces impact cell and tissue behavior, as well as how endogenous cellular forces can permanently remodel the local ECM. This is particularly relevant for macro-scaleAdvancing Synthetic Hydrogels through Nature-Inspired Materials Chemistry Synthetic extracellular matrix (ECM) mimics that can recapitulate the complex biochemical and mechanical nature of native tissues are essential for advanced models of development and disease. Biomedical research has relied on animal-derived biomaterials, which hinder translational potential and complicate biological insights. Natural hydrogels have been effective cell culture tools, but advances in materials chemistry and fabrication techniques now offer promising xenogenic-free ECM substitutes for organotypic models and microphysiological systems. However, synthetic matrices must approximate the structural sophistication, biochemical complexity, and dynamic functionality of native tissues. This review summarizes key properties of the native ECM and discusses recent approaches to systematically decouple and tune these properties in synthetic matrices. The importance of dynamic ECM mechanics, such as viscoelasticity and matrix plasticity, is emphasized, particularly in the context of organoid and engineered tissue matrices. Emerging design strategies to mimic these dynamic mechanical properties are reviewed, such as multi-network hydrogels, supramolecular chemistry, and hydrogels assembled from biological monomers. The native ECM provides crucial biochemical and biophysical instruction to resident cells, directing tissue morphogenesis, maturation, and homeostasis. Cells sense ECM mechanics through traction forces and mechanoreceptors, activating mechanosensitive pathways that regulate gene and protein expression. ECM mechanics influence inter/intracellular tension, governing tissue geometry, polarization, and spatial organization. Over longer time scales, these signaling networks impact physiological outcomes like regeneration and pathological outcomes like cancer progression. Synthetic hydrogels mimic the highly hydrated nature of native tissues, composed of cell-laden hydrogels that replicate the biochemical and mechanical properties of native tissues. These natural biopolymers have intricate hierarchical structures and complex chemical compositions, contributing to the dynamic mechanical nature of native tissues. The mechanics of native tissues are characterized by complex viscoelastic behavior, dependent on time and mechanical loading rate. Viscoelastic materials show both an instantaneous elastic response and time-dependent energy dissipation. Viscoelasticity significantly impacts cell- and tissue-level behavior, such as stem cell fate, neural maturation, immune cell specification, and vascular morphogenesis, as well as pathological processes like cancer progression. The inherent chemical complexity of biological polymers results in a poorly defined matrix, necessitating synthetic matrices that can recapitulate the dynamic, time-dependent mechanics of biological ECMs. Traditional synthetic hydrogel systems feature linearly elastic networks of high molecular-weight polymers, allowing high engineering control but not distributing cell-generated stresses physiologically. Decellularized animal-secreted ECMs mimic tissue mechanical responses but restrict experimental control and reproducibility. Recent progress in biomimetic materials chemistry and biofabrication design has narrowed this gap. Viscoelastic materials can more realistically capture how exogenous forces impact cell and tissue behavior, as well as how endogenous cellular forces can permanently remodel the local ECM. This is particularly relevant for macro-scale