Tumor growth and progression rely upon angiogenesis, which is regulated by pro- and antiangiogenic factors, including members of the semaphorin family. By analyzing three different mouse models of multistep carcinogenesis, we have shown here that during angiogenesis semaphorin3A (Sema3A) is expressed in endothelial cells, where it serves as an endogenous inhibitor of angiogenesis that is present in premalignant lesions and lost during tumor progression. Pharmacologic inhibition of endogenous Sema3A during the angiogenic switch, the point when pretumoral lesions initiate an angiogenic phase that persists throughout tumor growth, enhanced angiogenesis and accelerated tumor progression. By contrast, when, during the later stages of carcinogenesis following endogenous Sema3A downmodulation, Sema3A was ectopically reintroduced into islet cell tumors by somatic gene transfer, successive waves of apoptosis ensued, first in endothelial cells and then in tumor cells, resulting in reduced vascular density and branching, inhibition of tumor growth, and substantially extended survival. Further, long-term re-expression of Sema3A markedly improved pericyte coverage of tumor blood vessels, something that is thought to be a key property of tumor vessel normalization, and restored tissue normoxia. We conclude therefore that Sema3A is an endogenous and effective antiangiogenic agent that stably normalizes the tumor vasculature