The principles and ultimate goals of regenerative medicine and developmental biology involve a complex sequence of events, culminating in the formation of structurally and functionally normal tissues and organs. The molecular composition of the extracellular matrix (ECM) plays a critical role in cellular migration and differentiation events. Mammalian ECM, derived from various tissues and organs, has been used as a biologic scaffold for therapeutic regenerative applications. Hundreds of thousands of human patients have benefited from the use of biologic scaffolds composed of naturally occurring ECM. The mechanisms by which ECM induces constructive remodeling instead of scar tissue formation are only beginning to be understood. This article reviews composition of mammalian ECM, its poorly understood role in developmental biology, and the clinical applications that have resulted from the use of this naturally occurring scaffold. Anat Rec (Part B: New Anat) 287B:36–41, 2005. © 2005 Wiley-Liss, Inc.