The extracellular matrix (ECM) provides structural scaffolding for cells as well as crucial biochemical and biomechanical cues. The environment created by ECM is diverse and is different for each type of tissue depending on its role within the body. The ECM environment is also dynamic during development to a mature state. The healthy, mature state can be disrupted during disease. In this chapter we explore the spatial and temporal expression of ECM within the mammalian heart during development and with disease. When possible, we also evaluate how the expression of ECM proteins, in particular in location and time, affect cell behavior with emphasis on the in-vivo environment. We show that the study of cell-ECM interactions of heart tissues evolves over time from: 1) descriptive analyses of structure; to 2) dissected ECM-linked cell behaviors; to more recent work to unravel 3) the mechanistic underpinnings of ECM-linked cell behaviors. We suspect this experimental progression is reflected in tissues other than those of the heart, though the kinetics may differ.