Cells are mechanically coupled to their extracellular environments, which play critical roles in both communicating the state of the mechanical environment to the cell as well as in mediating cellular response to a variety of stimuli. Along with the molecular composition and mechanical properties of the extracellular matrix (ECM), recent work has demonstrated the importance of dimensionality in cell-ECM associations for controlling the sensitive communication between cells and the ECM. Matrix forces are generally transmitted to cells differently when the cells are on two-dimensional (2D) vs. within three-dimensional (3D) matrices, and cells in 3D environments may experience mechanical signaling that is unique vis-a-vis cells in 2D environments, such as the recently described 3D-matrix adhesion assemblies. This review examines how the dimensionality of the extracellular environment can affect in vitro cell mechanobiology, focusing on collagen and fibrin systems.