The article discusses how tissue cells, including fibroblasts, myocytes, and neurons, sense and respond to the stiffness of their substrate. Cells are generally anchorage-dependent, meaning they require adhesion to a solid surface to survive. The stiffness of the substrate can range from soft to rigid, and this variation is crucial for understanding cell behavior. Key mechanisms involved in this process include adhesion complexes and the actin-myosin cytoskeleton, which transmit forces through transcellular structures. Cells not only apply forces but also respond to the resistance they sense, adjusting their adhesions, cytoskeleton, and overall state. This feedback loop is essential for development, differentiation, disease, and regeneration. The article highlights that cells probe elasticity by anchoring and pulling on their surroundings, with processes dependent on myosin-based contractility and transcellular adhesions. Contractile forces in cells are generated by interactions between actin and myosin filaments, and these forces are transmitted to the substrate, causing wrinkles or strains. Cells respond to this resistance by adjusting their adhesions and cytoskeleton, and their overall state. The article also discusses how the stiffness of the substrate affects cell behavior, such as adhesion, cytoskeleton organization, and differentiation processes. Additionally, the article explores the role of contractility in substrate sensing, with myosin inhibitors providing key evidence. It also examines the nonlinear responses of cells to compliance signals and molecular effectors, such as the interplay between physical and biochemical signals in the feedback loop of matrix stiffness on contractility and cell signaling. The article concludes by discussing the broader implications of these findings for understanding cell-cell interactions during embryonic development and tissue regeneration.The article discusses how tissue cells, including fibroblasts, myocytes, and neurons, sense and respond to the stiffness of their substrate. Cells are generally anchorage-dependent, meaning they require adhesion to a solid surface to survive. The stiffness of the substrate can range from soft to rigid, and this variation is crucial for understanding cell behavior. Key mechanisms involved in this process include adhesion complexes and the actin-myosin cytoskeleton, which transmit forces through transcellular structures. Cells not only apply forces but also respond to the resistance they sense, adjusting their adhesions, cytoskeleton, and overall state. This feedback loop is essential for development, differentiation, disease, and regeneration. The article highlights that cells probe elasticity by anchoring and pulling on their surroundings, with processes dependent on myosin-based contractility and transcellular adhesions. Contractile forces in cells are generated by interactions between actin and myosin filaments, and these forces are transmitted to the substrate, causing wrinkles or strains. Cells respond to this resistance by adjusting their adhesions and cytoskeleton, and their overall state. The article also discusses how the stiffness of the substrate affects cell behavior, such as adhesion, cytoskeleton organization, and differentiation processes. Additionally, the article explores the role of contractility in substrate sensing, with myosin inhibitors providing key evidence. It also examines the nonlinear responses of cells to compliance signals and molecular effectors, such as the interplay between physical and biochemical signals in the feedback loop of matrix stiffness on contractility and cell signaling. The article concludes by discussing the broader implications of these findings for understanding cell-cell interactions during embryonic development and tissue regeneration.