Engineering a stem cell niche is to recapitulate a stem cell microenvironment and recreate it closely in vitro for the purpose of tissue regeneration and organ repair. Stem cell niches where stem cells reside present dynamic biophysical and biochemical cues to regulate stem cell fate through cell–cell and cell–extracellular matrix (ECM) interactions. These interactions are in response to different cellular needs such as tissue development, maintenance and repair. Here, we discuss the influence of biophysical factors (topography, patterning, surface modification, stiffness, etc.) and biochemical factors (ligands, bioactive chemicals, etc.) on stem cell fate such as self-renewal, expansion and lineage-specific differentiation in 2D as well as in 3D systems. Although there have been many studies establishing the importance of these cues, precise spatiotemporal control over all these cues at the nanoscale level remains a challenge. 4D systems with dynamic features of 3D cell constructs have emerged to better emulate a dynamic stem cell microenvironment. In future, advances in stem cell biology, click-chemistry, and 4D laser printing may help closely replicate stem cell niches to accurately guide stem cell fate in space and time.