The extracellular matrix (ECM) is crucial in tissue engineering and regenerative medicine (TERM), offering structural support and biochemical signals essential for cell adhesion, proliferation, and differentiation. This chapter delves into ECM-driven approaches for bone and cartilage regeneration, emphasizing the role of mechanotransduction in regulating stem cell behavior and tissue repair. Key scaffold design principles, including biocompatibility, mechanical strength, biodegradability, and vascularization, are explored in depth. Silk fibroin-based hybrid scaffolds are highlighted for their exceptional properties, such as high biocompatibility, adjustable degradation rates, and functionalization options like polymer blending, bioactive molecule incorporation, and nanocomposite integration. Additionally, various fabrication techniques—including electrospinning, freeze-drying, hydrogel formation, and 3D bioprinting—are examined for their potential to replicate native ECM structures. This chapter underscores the significance of ECM-inspired scaffolds in advancing regenerative medicine and orthopedic tissue engineering, particularly for osteochondral defects, where regeneration of the cartilage and the underlying bone is vital for restoring joint function.