Biomaterials that exhibit bioinspired behavior enable a range of novel biomedical applications. Cell‐friendly biomaterials incorporating crucial physicochemical cues can instruct and dictate cell behavior both in vitro and in vivo. Despite substantial advances, engineering a complex cell regulatory system that incorporates mechanical and chemical signals targeting specific intracellular events has remained far from a reality. Recently, biological studies have begun to decipher the dynamic interplay between stem cells and their microenvironments. Moreover, the myriad recently developed advanced material biotechnologies, such as 3D bioprinting, protein engineering, release technology, high‐throughput screening, and microfluidics, have enabled the engineering of sophisticated biomaterial systems that increasingly closely mimic the spatial and temporal characteristics of the native cell milieu. Thus, biomaterials engineered in the laboratory not only provide a fertile environment for fostering stem cells but also exhibit properties that elicit favorable crosstalk between the structural components, the cells and the host tissue in a precise physiological manner, enabling balanced matrix generation and degradation for successful tissue regeneration to be achieved. This progress report discusses these advanced biotechnologies for the design, fabrication, and functionalization of biomaterials, highlighting their merits over traditional methodologies for mimicking the structural and mechanical properties of their natural in vivo counterparts.