Substantial experimental evidence supports the idea that the fibroblast may play a significant role in the vascular response to injury, especially under hypoxic conditions. Fibroblasts have the ability to rapidly respond to hypoxic stress and to modulate their function to adapt rapidly to local vascular needs. Fibroblasts appear to be uniquely equipped to proliferate, transdifferentiate, and migrate under hypoxic conditions. Proliferative responses to hypoxia depend on the activation of Gαi and Gq kinase family members, and on the subsequent stimulation of protein kinase C and mitogen-activated protein kinase family members. Extracellular nucleotides (eg, adenosine triphosphate [ATP]) are likely to be increased in the hypoxic adventitial compartment and can act as autocrine/paracrine modifiers of the hypoxia-induced proliferative response. The proliferative effects of ATP appear to be mediated largely through G-protein-coupled P2Y receptors in fetal and neonatal fibroblasts. Hypoxia, acting through Gαι-coupled pathways, also can directly up-regulate α-smooth muscle actin expression in fibroblast subpopulations, suggesting that hypoxia may play a direct role in mediating the “transdifferentiation” of fibroblasts into myofibroblasts in the vessel wall. In addition, chronic hypoxia causes stable (at least in vitro) phenotypic changes in fibroblasts that appear to be associated with changes in the signaling pathways used to elicit proliferation. However, it is also becoming clear that, similar to the heterogeneity described for vascular smooth muscle cells, numerous fibroblast subtypes exist in the vessel wall, and that each may respond in unique ways to hypoxia and other stimuli and thus serve special functions in response to injury. In fact, adventitia may be considered to be compartments in which cells with “stem-cell-like” characteristics reside. Future work is needed to determine more precisely the role of the fibroblast in the wide variety of vascular complications observed in many humans diseases, and in the genes and gene products that confer unique properties to this important vascular cell.