In patients with chronic wounds, autologous tissue repair is often not sufficient to heal the wound. These patients might benefit from regenerative medicine or the implantation of a tissue-engineered scaffold. Both wound healing and tissue engineering is dependent on the formation of a microvascular network. This process is highly regulated by hypoxia and the transcription factors hypoxia-inducible factors-1 alpha ( HIF-1 alpha) and -2 alpha ( HIF-2 alpha). Even though much is known about the function of HIF-1 alpha in wound healing, knowledge about the function of HIF-2 alpha in wound healing is lacking. This review focuses on the function of HIF-1 alpha and HIF-2 alpha in microvascular network formation, wound healing, and therapy strategies.