The extracellular matrix (ECM) plays a pivotal role in cellular regulation and tissue architecture, serving as both a structural scaffold and a reservoir of biochemical cues. Cellular interactions with the ECM are critical for modulating processes such as adhesion, migration, proliferation, differentiation, and apoptosis. These interactions are primarily mediated through integrins and other ECM receptors that transduce extracellular signals into intracellular pathways, influencing cellular behavior in response to environmental changes. Dysregulation of these interactions can contribute to pathological conditions, including cancer, fibrosis, and cardiovascular diseases, where ECM remodeling alters the cellular microenvironment. The dynamic interplay between cells and ECM is fundamental to maintaining tissue homeostasis and facilitating processes such as wound healing and tissue repair. This chapter explores the molecular mechanisms by which cells perceive and respond to ECM cues and the implications of these interactions in health and disease. Recent advances in biomaterial science have led to the design of ECM-inspired scaffolds that replicate the native microenvironment, promoting tissue regeneration and functional integration in damaged tissues. These engineered matrices not only provide structural support but also incorporate biochemical signals to guide cell behavior, making them invaluable in regenerative medicine and tissue engineering. The growing understanding of how cells interact with the ECM is thus pivotal for developing next-generation therapeutic strategies aimed at both tissue repair and disease treatment.