The extracellular matrix (ECM) is a highly heterogeneous mixture of macromolecules capable of self-assembling into tissue-specific suprastructures that constitute the architectural elements supporting organ function. Contrary to the traditional view of being a static scaffold that supports tissue integrity along with cell adhesion and migration, the ECM is an inherently dynamic system that specifies cellular function and defines the limits and patterns of tissue organization. Throughout evolution, the composition and organization of the ECM have changed to accommodate basic and new tissue functions, both in terms of providing structural support and integrating multivalent signals to cells. In this review, we will highlight some of these bidirectional cell–matrix interactions that guide the development of a mechanically compliant vascular system. Specifically, we will focus on studies that have investigated how ECM composition and physical properties influence cell fate decisions associated with vascular tissue development and homeostasis and implicitly, vascular disease.