Stem cells are defined as unspecialized cells that are capable of long term self-renewal and differentiation into specialized cell types. These unique properties make them an attractive cell source for regenerative medicine applications. Although the functions of various stem cells have been extensively studied in the development of organisms and in diseases, the specific factors and conditions that control stem cell fate, specifically the conditions that allow them to remain unspecialized, are not well studied. It has been suggested that adult stem cell survival and maintenance, as well as proliferation and differentiation, are controlled by the three-dimensional (3D) microenvironment, the so-called niche. Major functional niche components include supporting niche cells, growth-modulating soluble factors stored within the niches, and the extracellular matrix (ECM). In this article, we review work highlighting the growing complexity of stem cell-ECM interactions and their impact on the fields of biomaterials research and regenerative medicine.