The extracellular microenvironment regulates cell decisions through the accurate presentation at the cell surface of a complex array of biochemical and biophysical signals that are mediated by the structure and composition of the extracellular matrix (ECM). On the one hand, the cells actively remodel the ECM, which on the other hand affects cell functions. This cell–ECM dynamic reciprocity is central in regulating and controlling morphogenetic and histogenetic processes. Misregulation within the extracellular space can cause aberrant bidirectional interactions between cells and ECM, resulting in dysfunctional tissues and pathological states. Therefore, tissue engineering approaches, aiming at reproducing organs and tissuesin vitro, should realistically recapitulate the native cell–microenvironment crosstalk that is central for the correct functionality of tissue-engineered constructs. In this review, we will describe the most updated bioengineering approaches to recapitulate the native cell microenvironment and reproduce functional tissues and organsin vitro. We have highlighted the limitations of the use of exogenous scaffolds in recapitulating the regulatory/instructive and signal repository role of the native cell microenvironment. By contrast, strategies to reproduce human tissues and organs by inducing cells to synthetize their own ECM acting as a provisional scaffold to control and guide further tissue development and maturation hold the potential to allow the engineering of fully functional histologically competent three-dimensional (3D) tissues.