The ability of stem cells to self-renew with minimal or no differentiation and, when appropriately cued, to give rise to many types of progenitor and mature cells, is the basis for applications in regenerative and transfusion medicine, but also in drug discovery and in vitro toxicology. Inspired by the complex interactions between stem cells and their microenvironment, the so-called stem-cell niche, the properties of supporting biomaterials, including surface biochemistry, topography (type, size, organization, and geometry of nanostructures), and mechanical properties, have been identified as important determinants of stem-cell fate in vitro. 3D culture environments that could recapitulate the complexity of the in vivo stem-cell microenvironment could further expand the complexity and repertoire of engineered environments with exciting translational applications. Herein, the material aspects that affect the expansion and differentiation fate of adult hematopoietic stem/progenitor cells (HSPCs) and mesenchymal stem cells (MSCs), two powerful cell types that co-reside in the bone-marrow niche, but with distinct, sometime complementary, differentiation fates, properties, and translational applications, are examined. Although MSCs are adherent cells and, in contrast, HSPCs are non- or weakly adherent cells, both can sense and respond to material properties, including surface (bio)chemistry, ECM composition, topography, and matrix elasticity, possibly through similar molecular mechanisms.