The dynamically changing biomechanical environment in human organs plays a profound role in various cellular functions such as proliferation, three-dimensional (3D) tissue formation, and differentiation in health and disease. Modeling this essential feature of living organisms has remained critically challenged due to technical limitations in existing experimental platforms, thus limiting our ability to understand complex mechanisms underlying disease and to develop novel therapeutics. In this work, we leveraged microengineering approaches for the development of human ‘organ-on-chip’ technology that enables the reconstitution of the complex 3D tissue structures of target organs in engineered systems equipped with the synthesized, organ-specific biophysical microenvironment. Specifically, we first developed a model of a blinking human eye that replicates multiscale organization, differentiated cellular phenotypes, and blink-induced dynamic mechanical environment of the ocular surface. The unique capability of this model to mimic eye blinking allowed us to recapitulate physiological tear film dynamics, enabling the creation of a model of human dry eye disease. We also demonstrated the feasibility of using our bioengineered disease model as a screening platform to assess the efficacy of an investigational dry eye. In the second project, we created a microdevice for culturing human lung endothelial cells under physically dynamic conditions created by fluid shear stress and mechanical stretching to replicate the full repertoire of biomechanical cues generated by blood flow and breathing movements in lungs. In this study, we observed the effects of altered shear stress and breathing-induced mechanical strains on the exacerbation of injuries in the microengineered endothelium when perfused with human red blood cells (RBCs), replicating transfusion-related acute lung injury in critically ill patients. Lastly, we report the development of a microengineered model of the human cervix for the study of premature cervical remodeling during preterm birth. In our preliminary studies, we simulated bacterial infection in the human cervix by exposing the microengineered cervical tissue to lipopolysaccharide (LPS). We observed that LPS treatment induces the disruption of epithelial barrier function accompanied by the onset of inflammatory responses, ultimately leading to the remodeling of the extracellular matrix (ECM) in the stroma. Collectively, this work represents a significant advance in our ability to model and probe human physiological systems in the context of the dynamically changing biophysical environment. The demonstrated organ-on-a chip strategy may contribute to the development of innovative enabling platforms for a variety of biomedical and biopharmaceutical applications.