Growth factor activity is localized within the natural extracellular matrix (ECM) by specific noncovalent interactions with core ECM biomolecules, such as proteins and proteoglycans. Recently, these interactions inspired the development of synthetic biomaterials that can noncovalently regulate growth factor activity for tissue-engineering applications. For example, biomaterials covalently or noncovalently modified with heparin glycosaminoglycans can augment growth factor-release strategies. In addition, recent studies demonstrate that biomaterials modified with heparin-binding peptides can sequester cell-secreted heparin proteoglycans and, in turn, sequester growth factors and regulate stem cell behavior. Another set of studies shows that modular versions of growth factor molecules can be designed to interact with specific components of natural and synthetic ECMs, including collagen and hydroxyapatite. In addition, layer-by-layer assemblies of GAGs and other natural polyelectrolytes retain growth factors at a cell/material interface via specific noncovalent interactions. This Feature Article provides a detailed overview of the various bioinspired strategies that are used to noncovalently localize growth factor activity within biomaterials, and will highlight in vivo examples of the efficacy of these materials to promote tissue regeneration.