The adventitia functions as a dynamic compartment for cell trafficking into and out of the artery wall, and communicates with medial and intimal cells. The resident cells in the tunica adventitia play an integral role in the regulation of vessel wall structure, repair, tone, and remodeling. Following injury to the vascular wall, adventitial fibroblasts are activated, which proliferate and differentiate into migratory myofibroblasts, and initiate inflammation through the secretion of soluble factors such as chemokines, cytokines, and adhesion molecules. The secreted factors subsequently promote leukocyte recruitment and extravasation into the media and intima. The adventitia generates reactive oxygen species and growth factors that participate in cell proliferation, migration, and hypertrophy, resulting in intimal thickening. The adventitial vasa vasorum undergoes neovascularization and serves as a port of entry for the delivery of inflammatory cells and resident stem/progenitor cells into the intima, and thus facilitates vascular remodeling. This review highlights the contribution of multilineage cells in the adventitia along with de-differentiated smooth muscle-like cells to the formation of neointimal hyperplasia, and discusses the potential of periadventitial local drug delivery for the prevention of vascular restenosis.