During development, extrinsic signals from the environment are transduced and converted to intrinsic changes in gene expression that specify the identity and function of cells. Gene regulation gives the cell control over structure and function, and is the basis for cellular differentiation and morphogenesis. These critical developmental processes take advantage of cooperation of transcription factors and epigenetic modifiers, yet very little is known regarding how these events are initiated and regulated. Various niche factors including ECM proteins, growth factors and cytokines, as well as the physiochemical and biomechanical environment, act on cardiovascular progenitor cells (CPCs) to alter gene expression, induce cellular proliferation and differentiation, and define how the cardiovascular fate is stabilized and segregated from alternative fates. When misregulated, these environmental cues may lead to pathologies by inducing aberrant function in stem cells or other targets. If we are able to identify these critical developmental processes, we can then use it to stimulate regenerative strategies, including tissue engineering of living heart valves and blood vessels, or to provide insight into cardiovascular disease pathologies.