Reciprocal interactions of cells with their surrounding microenvironment are fundamental to multiple cellular processes necessary for tissue development, homeostasis, and regeneration. It is becoming increasingly apparent that while the extracellular environment normally maintains tissue homeostasis, when negatively perturbed, it may also contribute to disease progression and age-dependent pathologies. However, the changes that the extracellular microenvironments undergo in perturbed pathological systems and how these changes effect differential cellular responses remain elusive. In an effort to dissect the physicochemical cues of the extracellular environment on various cellular responses, our laboratory is employing various synthetic and in vivo systems. Specifically, we focus on extracellular matrix physicochemical cues on stem cell commitment (from the perspective of musculoskeletal tissue regeneration) and disease progression (from the perspective of cancer metastasis and fibrosis).