It is popular stance that successful growth be it structural, economic or biological requires a stable foundation. The hierarchical structure of native biological materials and tissues introduces variations in form and function across a multitude of scales. Yet, many synthetic scaffolds and substrates in which such materials are assembled, the foundation, are designed at a single scale. The result is an uncertain or shaky foundation for material assembly and tissue growth, where changes in the scaffold properties and architecture result in unpredictable behaviors in tissue development, and proven, reliable scaffolds for one tissue type may be completely unsuitable for another. This is in contrast to the behavior of foundations for civil engineering structures, which provide a decoupling of the foundation from the building design since different foundations can support equivalent functional structures. Current advancements in the design of biologically active foundations shed light on proven scaffolds and substrates, but cannot be used to design and predict success from the bottom-up. This is because while the phenomenological coupling between materials and substrates has been well investigated and has yielded methodologies for biomaterial synthesis, the underlying mechanisms of self-assembly and growth are not fully understood. A potential solution lies in the utilization of hierarchical material foundations, with molecular, fibrillar and other interactions designed across all length- and time-scales with engineered, predictive, and repeatable outcomes. The potential to realize such hierarchical multiscale scaffolds can be found in the exploitation of responsive, or mutable, polymer systems that exhibit precise control and variegated chemical functionalities for applications in diverse areas such as regenerative medicine, cancer treatment or drug delivery. (C) 2011 Published by Elsevier Ltd.