The vasculature in adult skin remains normally quiescent, due to the dominant influence of endogenous angiogenesis inhibitors over angiogenic stimuli. However, skin retains the capacity for brisk initiation of angiogenesis, the growth of new blood vessels from preexisting vessels, during tissue repair and in numerous diseases, including inflammatory skin diseases such as psoriasis and skin cancers such as cutaneous squamous cell carcinomas. Moreover, cyclic vascular expansion occurs during the growth phase of the hair follicle. Recent evidence suggests vascular endothelial growth factor as the major skin angiogenesis factor. During skin angiogenesis, expression of vascular endothelial growth factor is induced in epidermal keratinocytes by several stimuli including transforming growth factor-alpha and hypoxia, leading to increased vascularization of the dermis. In contrast, vascular endothelial growth factor-C induces skin lymphangiogenesis. Thrombospondin-1 and thrombospondin-2 are endogenous inhibitors of angiogenesis that are expressed in normal skin, maintaining the quiescence of cutaneous vessels. Both inhibitors potently inhibit skin cancer growth via inhibition of tumor angiogenesis. Targeting cutaneous blood vessels represents a promising new therapeutic approach for the treatment of a variety of skin diseases.