An increasing body of evidence indicates that in the leech Hirudo medicinalis the angiogenic process is finely regulated and coordinated by the botryoidal tissue. In this paper we provide evidence on the involvement of botryoidal tissue cells in angiogenesis induced in H. medicinalis by a variety of stimuli including surgical wounds or the administration of modulators of neovascularization. Interestingly, we show that either human activators of vascular cell growth, or anti-angiogenic peptides like angiostatin and endostatin, or the drug mitomycin, can induce a prompt biological response in H. medicinalis. We show as well that angiogenesis in this invertebrate shares a surprising degree of similarity with neovascularization in vertebrates, both at the biochemical and cellular levels, because it involves similar growth factors/growth factor receptors, and relies on analogous cell–cell or cell–matrix interactions. For these reasons we suggest that H. medicinalis can be used as a reproducible model for testing activators or inhibitors of angiogenesis, and for investigating the biochemical, ultrastructural and cellular processes involved in new vessel formation.