Stem cells have great potential in regenerative medicine and tissue injury. Regulation of stem cell homeostasis in a 3D microenvironment is controlled by the niche components that influence stem cell fate, regulation, and function. It is therefore necessary to understand the mechanisms of cell-cell interaction, molecular cross talk between stem cells and their extracellular matrix (ECM) environment. The adhesion molecules play a pivotal role in establishing the cell-cell contact and subsequent integration with the ECM. This understanding is the basis for establishing design criteria for biomimetic. The integrated approach by biologists, material science engineers, biomedical engineers, and clinicians is the key in the development of tissue engineered constructs for effective translation to clinics.