By definition, biomaterials and tissue engineering materials aim to replace, restore, and/or regenerate tissue where disease or injury has caused irreparable damage to native tissue. However, mimicking the complexity of the in vivo milieu has proved to be a serious challenge for current biomaterials. For example, one common strategy involves incorporating a short known biologically active motifs into the biomaterial to encourage cellular attachment, migration, and differentiation. In doing so, the intricacy of the dynamic in vivo environment is greatly diminished. This chapter highlights dynamic elements of the extracellular matrix (ECM) that provide critical signaling cues in vivo, the state of current biomaterial approaches, and potential approaches to incorporate more complex components into future biomaterials. The goal of this section is to introduce emerging concepts in matrix biology that have the potential to be exploited in biomaterials design, rather than being an exhaustive review of ECM dynamics.