An increasing volume of experimental data indicates that the adventitial fibroblast, in both the pulmonary and systemic circulations, is a critical regulator of vascular wall function in health and disease. A rapidly emerging concept is that the vascular adventitia acts as biological processing center for the retrieval, integration, storage, and release of key regulators of vessel wall function. In response to stress or injury, resident adventitial cells can be activated and reprogrammed to exhibit different functional and structural behaviors. In fact, under certain conditions, the adventitial compartment may be considered the principal injury-sensing tissue of the vessel wall. In response to vascular stresses such as overdistension and hypoxia, the adventitial fibroblast is activated and undergoes phenotypic changes, which include proliferation, differentiation, upregulation of contractile and extracellular matrix proteins, and release of factors that directly affect medial smooth muscle cell tone and growth and that stimulate recruitment of inflammatory and progenitor cells to the vessel wall. Each of these changes in fibroblast phenotype modulates either directly or indirectly changes in overall vascular function and structure. The purpose of this review is to present the current evidence demonstrating that the adventitial fibroblast acts as a key regulator of pulmonary vascular function and structure from the “outside-in.”