Antiangiogenic therapy, including blockade of vascular endothelial growth factor (VEGF) signaling, was highly anticipated to improve the prognosis for patients with advanced cancers following the success of preclinical animal models. However, antiangiogenic monotherapy with VEGF antagonists has produced disappointing results in clinical trials to date. One of the reasons for this poor outcome is that angiogenesis is not solely regulated by VEGF. Inhibition of VEGF signaling, therefore, may select for tumor cell populations that stimulate angiogenesis through VEGF-independent pathways. Successful antiangiogenic therapy, therefore, may require simultaneous blockade of signaling downstream from multiple proangiogenic factor receptors. Recently, we found that non-receptor protein-tyrosine kinases, including members of the Src and Fes families, play vital roles in the responses of cultured endothelial cells to several proangiogenic factors. In this review, we summarize the contributions of these kinase families to angiogenic pathways in endothelial cells, and discuss the potential of these kinases as new targets for antiangiogenic drug discovery.