Scaffolds and cells play a central role in the tissue engineering and regenerative medicine (TERM) field, where scaffolds provide physical scaffolding, and biochemical and biophysical cues for regulation of cell function or fate. Scaffolds and cells interact at the surface level through important cell structures like the cell membrane or the cytoskeleton, which are used in vivo for interacting with the dynamic extracellular matrix (ECM). The first event of cell-scaffold interaction is cell adhesion, which is highly dependent on surface properties such as chemistry, wettability, topography or stiffness. Following cell adhesion, other cellular events ensue such as spreading, proliferation or differentiation. Ultimately, TERM scaffolds present three-dimensionality and cells respond to architectural traits like porosity, pore size, pore interconnectivity, or permeability. This chapter focuses on cell—scaffold interactions at the surface level, as well as cell responses to 3D features of scaffolds. The chapter also reviews the cell membrane, the cytoskeleton and the ECM. Finally, conclusions and questions to reinforce the different concepts and aspects covered in this chapter are presented.