Transplant vasculopathy is one of the major causes of chronic rejection following solid organ transplantation. The pathogenic mechanisms of transplant vasculopathy are still poorly understood. Here we summarize current evidence suggesting that activation of the tunica adventitia may be involved in the pathogenesis of transplant vasculopathy. Adventitia is an early responder to various vascular injuries and plays an integral role in eliciting vascular inflammation and remodeling. Accumulation of macrophages in the adventitia promotes the development of vascular remodeling by releasing a variety of paracrine factors that have profound impacts on vascular mural cells. Targeting adventitial macrophage accumulation has been shown to be effective for repressing transplantation-induced arterial remodeling in animal models. Adventitia also fosters angiogenesis, and neovascularization of the adventitial layer may facilitate the transport of inflammatory cells through the arterial wall. It warrants further investigations to clarify whether inhibiting adventitial oxidative stress and/or adventitial neovascularization are better strategies for preventing transplant vasculopathy.