Directing specific, complex cell behaviors, such as differentiation, in response to biomaterials for regenerative medicine applications is, at present, a mostly unrealized goal. To date, current technological advances have been inspired by the reductionist point of view, focused on developing simple and merely adequate environments that facilitate simple cellular adhesion. However, even if extracellular matrix (ECM)-derived peptides, such as Arg-Gly-Asp (RGD), have largely demonstrated their utility in supporting cell adhesion, their lack of biological specificity is simply not optimal for controlling more integrated processes, such as cell differentiation. These more complex cellular processes require specific integrin-signaling scaffolds and presumably synergistic integrin and growth factor-receptor signaling. This article will introduce some current efforts to engineer ECM variants that incorporate additional levels of complexity for directing greater integrin specificity and synergistic ECM growth factor signaling toward directing cell phenotype.