As normal cells progress to malignancy they must acquire an angiogenic phenotype that will enable them to attract the blood vessels necessary to support their progressive growth. Here we define the mechanism by which human fibroblasts cultured from Li Fraumeni patients and progressing to tumorigenicity in vitro become angiogenic. Initially cells were anti-angiogenic due to the secretion of high levels of inhibitory thrombospondin that overrode the modest amounts of the major inducer, vascular endothelial cell growth factor (VEGF), that were also produced. Cells became fully angiogenic in two steps, the first dependent on the loss of both alleles of wild-type p53 which caused a drop of at least 20-fold in secreted thrombospondin and a fourfold increase in secreted VEGF. Angiogenic activity increased again upon transformation by activated ras due to a further twofold increase in VEGF. Changes in relative levels of VEGF mRNA were sufficient to account for changes in secreted protein levels and in overall angiogenic activity. These studies demonstrate that an angiogenic phenotype able to support tumorigenicity can arise in a step-wise fashion in response to both oncogene activation and tumor suppressor gene loss and involve both a decrease in the secretion of inhibitors and the sequential ratcheting up of the secretion of inducers of angiogenesis.