FGF2 and PDGF-BB both activate tyrosine kinase receptors (FGFR1 and PDGFR-β, respectively) that in turn activate PI3K signaling, yet differ in their downstream consequences. PDGF-BB is a well-known stimulator of Akt, which can activate reactive oxygen species (superoxide [O₂^–] and hydrogen peroxide [H₂O₂]) through induction of cytochrome b558 genes, resulting in the induction of HIF1α and HIF2α and eventually VEGF, a potent endothelial cell chemoattractant, and Ang-2, which likely mediates a repulsive effect that prevents pericyte–endothelial cell stabilization of neoangiogenic vessels. FGF2 is a potent activator of phospholipase D, that acts as an alternative survival factor to Akt. Blockade of PDGF by a specific tyrosine kinase inhibitor may promote FGF2 signaling, while blockade of FGF2 signaling may promote PDGF-BB–mediated signaling. Blockade of both FGF2 and PDGF-BB with a promiscuous tyrosine kinase inhibitor or other dirty compound may be more effective than targeted tyrosine kinase inhibitor monotherapy in blocking tumor growth.