Successful regenerative medicine strategies for functional tissue reconstruction include the in situ placement of acellular materials composed of the extracellular matrix (ECM) or individual components of the ECM. The composition and ultrastructure of these materials vary depending on multiple factors including the tissue source and species from which the materials are harvested, the methods of manufacture, the efficiency of decellularization, post-processing modifications such as chemical cross-linking or solubilization, and the methods of terminal sterilization. Appropriately configured materials have the ability to modulate different stages of the healing response by inducing a shift from a process of inflammation and scar tissue formation to one of constructive remodeling and functional tissue restoration. The events that facilitate such a dramatic change during the biomaterial-host interaction are complex and necessarily involve both the immune system and mechanisms of stem cell recruitment, growth, and differentiation. The present manuscript reviews the composition of biologic scaffolds, the methods and recommendations for manufacture, the mechanisms of the biomaterial–host interaction, and the clinical application of this regenerative medicine approach.