Understanding the complex interactions between cells and the extracellular matrix (ECM) is crucial. These interactions involve biochemical signals and mechanical forces that regulate vital cellular processes, including migration, differentiation, and proliferation. Disruptions in these interactions frequently correlate with various pathologies, underscoring the importance of studying these mechanisms. This thesis explores four specific topics on cell-ECM interactions. First, we examine the role of glycosaminoglycans (GAGs) within ECM. We show that due to their hydrophilic properties and contribution to the ECM’s mechanical integrity, GAGs can modulate the anisotropic strain-stiffening behavior of the ECM and further impact cellular force transmission. Second, we examine the rheological characteristics of tissues densely packed with cells. Our analysis reveals an unexpected transition from compression softening to compression stiffening in these tissues because of the presence of cells. This finding is crucial for understanding how tissues endure and adapt to mechanical stresses, which are key to maintaining tissue health and functionality. Third, we introduce a chemomechanical model that elucidates the mechanism of the spatiotemporal evolution of cell redistribution during blood clot contraction. This model demonstrates how mechanosensitive signaling controls ATP hydrolysis in platelets, subsequently leading to cellular reorganization within blood clots. Lastly, we develop a phase field theory-based model to determine how forces alter chromatin organization within the nucleus, thus impacting the accessibility of genes for transcription. This work establishes a direct link between mechanical stimuli and genetic regulation within the cell. Overall, our work introduces novel chemo-mechanical theories that elucidate these vital biophysical processes. The implications of this research are extensive, enhancing our understanding of tissue mechanics and disease pathogenesis and informing the development of therapeutic strategies.