All cells in multicellular organisms are housed in the extracellular matrix (ECM), an acellular edifice built up by more than a thousand proteins and glycans. Cells engage in a reciprocal relationship with the ECM; they build, inhabit, maintain, and remodel the ECM, while, in turn, the ECM regulates their behavior. The homeostatic balance of cell-ECM interactions can be lost, due to ageing, irritants or diseases, which results in aberrant cell behavior. The ECM can suppress or promote disease progression, depending on the information relayed to cells. Instructions come in the form of biochemical (e.g., composition), biophysical (e.g., stiffness), and topographical (e.g., structure) cues. While advances have been made in many areas, we only have a very limited grasp of ECM topography. A detailed atlas deciphering the spatiotemporal arrangement of all ECM proteins is lacking. We feel that such an extracellular matrix architecture (matritecture) atlas should be a priority goal for ECM research. In this commentary, we will discuss the need to resolve the spatiotemporal matritecture to identify potential disease triggers and therapeutic targets and present strategies to address this goal. Such a detailed matritecture atlas will not only identify disease-specific ECM structures but may also guide future strategies to restructure disease-related ECM patterns reverting to a normal pattern.