Many crucial cellular processes in our tissues are governed by complex, spatio-temporally regulated interactions between cells and their extracellular matrix (ECM). These interactions can be studied using well-established 3D in vitro model systems such as collagen gels or Matrigel generated from native ECM macromolecular components. Recent advances in the molecular design of smart synthetic biomaterials have generated artificial ECM (aECM) that mimic some of the key structural and biochemical characteristics of their naturally derived counterparts and, thanks to their synthetic origin, promise to overcome some complexities of the latter. Here I will discuss emerging approaches in aECM design, hopefully inspiring cell biologists to apply these systems to address their specific biological question.