After decades of efforts from both academic and industrial researchers, a great mass of knowledge and tremendous progress has been made in tissue engineering, which has great potential in both regenerative medicine and as an in vitro testing platform. However, in creation of large tissues/organs with multiple functionalities and hierarchical structures, several challenges, e.g., vascularization and spatially controlled cell organization confound current tissue engineering strategy. Recognition of these challenges inspires our ongoing efforts in creating vasculature in tissue-engineered substitutes and the development of bottom-up tissue engineering. The former enables the free exchange of nutrient and gas across the large substitutes, and the latter allows straightforward manipulation of the spatial arrangement of multiple cell types and customization of the growth environment for individual cell type. Along with this endeavor, the configuration of a cell-friendly microenvironment is critical to guarantee the desirable cell phenotype, leading to functional tissue formation. In this regard, a biomimetic approach is taken in biomaterial design to maximally recapture the native cell-residing environment on a micro/nanoscale.