Advancements in materials-driven mechanobiology have yielded significant progress. Mechanobiology explores how cellular and tissue mechanics impact development, physiology, and disease, where extracellular matrix (ECM) dynamically interacts with cells. Biomaterial-based platforms emulate synthetic ECMs, offering precise control over cellular behaviors by adjusting mechanical properties. Recent technological advances enable in vitro models replicating active mechanical stimuli in vivo. These models manipulate cellular mechanics even at a subcellular level. In this review we discuss recent material-based mechanomodulatory studies in mechanobiology. We highlight the endeavors to mimic the dynamic properties of native ECM during pathophysiological processes like cellular homeostasis, lineage specification, development, aging, and disease progression. These insights may inform the design of accurate in vitro mechanomodulatory platforms that replicate ECM mechanics.