Recent evidence indicates that stem/progenitor cells are present in the adventitia and participate in vascular repair and the formation of neointimal lesions in severely damaged vessels. Data have also demonstrated that these resident stem/progenitor cells could differentiate into endothelial or smooth muscle cells in response to different stimuli. Under pathological conditions, adventitial inflammation results in releasing a panel of cytokines, such as stromal cell-derived factor-1 and tumor necrosis factor-α, that may lead to local stem/progenitor mobilization and differentiation. Overall, these data support the impact of the adventitial progenitors in pathophysiological processes of lesion development in the arterial wall. In the present review, we aim to summarize the data concerning the presence of the resident stem cells and discuss the pathological impact of the adventitia in vascular diseases. We will also discuss the possible signal pathways orchestrating stem cell differentiation toward vascular lineage and highlight controversial issues related to the role of adventitial progenitors.