Fate mapping studies have shown that vascular smooth muscle is a mosaic tissue formed by progenitor cells from many different embryonic origins. Mechanisms that produce specified, but undifferentiated, smooth muscle cell (SMC) progenitor cells in the embryo depend on epigenetic chromatin modifications, small RNAs, and transcriptional corepressors that silence SRF- myocardin-dependent target genes. Upon interactions with endothelial cells, SMC differentiation marker genes become transcriptionally activated and tunica media formation is initiated. A characteristic number of SMC layers specific for each artery type is formed either by recruitment of surrounding mesenchymal cells or by oriented cell divisions of the primary SMC layer in contact with the endothelium. Around E15.5 in the mouse, SMC layer formation in the aorta is complete, and tunica adventitia formation begins. At this time sonic hedgehog (Shh) signaling becomes activated in the adventitia and stem cell antigen 1- expressing vascular stem cells (AdvSca1) are recruited to the developing adventitial niche. AdvSca1 cells cluster at the border between the medial and adventitial layers where they can be recruited into various mesenchymal cell fates, including SMCs, pericytes, adipocytes and osteogenic cells. These resident vascular stem cells may play important roles in artery wall repair, remodeling and disease as well as participating in normal growth and wound healing responses in adjacent tissues in contact with the arterial adventitia.