Extracellular matrices (ECMs) are dynamic 3D macromolecular networks that exhibit structural characteristics and composition specific to different tissues, serving various biomechanical and regulatory functions. The interactions between ECM macromolecules, such as collagen, elastin, glycosaminoglycans (GAGs), proteoglycans (PGs), fibronectin and laminin, along with matrix effectors and water, contribute to the unique cellular and tissue functional properties during organ development, tissue homoeostasis, remodeling, disease development and progression. Cells adapt to environmental changes by adjusting the composition and array of ECM components. ECMs forming the 3D bioscaffolds of our body provide mechanical support for tissues and organs and respond to the environmental variables influencing growth and final adult body shape in mammals. Different cell types exhibit specific adaptations to their respective ECM environments. ECMs regulate biological processes by controlling diffusion of infections/inflammations, sensing and adapting to external stimuli and gravity from the surrounding habitat, and, in the context of cancer, interplaying with and regulating cancer cell invasion and drug resistance. Alterations in the ECM composition in pathological conditions drive adaptive responses of cells and could therefore result in abnormal cell behavior and tissue dysfunction. Understanding the biomechanical functionality, adaptation and roles of distinct ECMs is essential for research into various pathologies, including cancer progression and multidrug resistance, which is of crucial importance for developing targeted therapies. In this Viewpoint article, we critically present and discuss specific biomechanical functions of ECMs and regulatory adaptation mechanisms in both health and disease, with a particular focus on cancer progression.