A major hurdle in studying biological systems and administering effective tissue engineered therapies is the lack of suitable cell culture models that replicate the dynamic nature of cell-microenvironment interactions. Advances in the field of surface chemistry and polymer science have allowed researchers to develop novel methodologies to manipulate materials to be extrinsically tunable. Usage of such materials in modeling tissues in vitro has offered valuable insights into numerous cellular processes including motility, invasion, and alterations in cell morphology. Here, we discuss novel techniques devised to more closely mimic cell-tissue interactions and to study cell response to distinct physico-chemical changes in biomaterials, with an emphasis on the manipulation of collagen scaffolds. The benefits and pitfalls associated with using collagen are discussed in the context of strategies proposed to control the engineered microenvironment. Tunable systems such as these offer the ability to alter individual features of the microenvironment in vitro, with the promise that the molecular basis of mechanotransduction in vivo may be laid out in future.