The emerging concept of matritherapies centers on the therapeutic normalization of extracellular matrix (ECM) composition, architecture, mechanical properties, and downstream signaling for therapeutic benefits. In this chapter, we explore ECM remodeling and fibroblast dysfunction in progressive pulmonary fibrosis and lung cancer, highlighting how insights into these changes can inform novel therapeutic strategies. While our primary focus is on fibrosis, we underscore important parallels to cancer biology and treatment approaches. We review the roles of major ECM components, particularly collagen, fibronectin, and tenascin-C, in driving fibrogenesis, tumor progression, and resistance to therapy. Therapeutic strategies discussed include targeting ECM-producing effector cells, such as fibroblasts and their pathological subpopulations; inhibiting ECM synthesis, maturation, and crosslinking; and exploiting ECM signatures for site-specific delivery of therapeutic agents. Notably, several ECM-targeting approaches, such as crosslinking inhibitors and ECM receptor antagonists, have entered clinical trials. However, many have failed for lack of effectiveness or safety issues, likely due to our limited molecular understanding of pathological ECM. Finally, we emphasize the value of emerging technologies such as spatial proteomics, which enable high-resolution mapping of ECM alterations in diseased versus healthy tissue and thereby offer a path to more precise and effective targeting of pathological ECM. Alongside human-derived organotypic models, these advances complement traditional rodent studies and open new avenues for therapeutic discovery. Taken together, these developments mark an exciting frontier in the treatment of fibrosis and cancer through ECM-centered strategies.