The chemical and physical properties of bulk and surface biomaterials can be changed by exposure of the biomaterials to electrical forces, shear stress forces, pH shifts, temperature changes, and light irradiation, as well as by the addition of small molecules. Such smart or dynamic (i.e., external signal-responsive) biomaterials serve as attractive platforms for the expansion and differentiation of stem cells, including adult stem cells, induced pluripotent stem cells (iPSCs) and embryonic stem cell (ESCs). Smart biomaterials can be prepared on non-micropatterned and micropatterned surfaces, on microcarriers or in hydrogels. Undifferentiated and differentiated stem cells can be cultivated on smart biomaterials immobilized with external signal-responsive molecules. Stem cells can be detached from these smart biomaterials without requiring mechanical forces or enzymatic digestion—rather, external signals received by the smart biomaterials facilitate cell detachment. This chapter describes the concepts underlying the design of smart biomaterials for cell detachment, cell expansion and cell differentiation governed by external signals.