It has been known for two decades that VEGF-A encodes several VEGF-A splice variants, which are termed VEGFxxx, according to the total number of amino acids in the mature protein. To date, nine VEGFxxx isoforms have been described, displaying different biodistributions and pro-angiogenic activities. Adding another level of complexity to VEGF-A biology, a new family of VEGF-A isoforms, termed VEGFxxxb, which exert anti-angiogenic functions, was discovered in 2002 and only differs from VEGFxxx polypeptides with regard to their six C-terminal amino acids. Therefore, reminiscent of what is observed, for instance, during apoptosis, the alternative splicing of VEGF-A pre-mRNA generates two types of isoforms with antagonistic biological functions. As anti-angiogenic therapies target both the VEGFxxx and VEGFxxxb families, VEGF-A pre-mRNA splicing may therefore impact tumor responses to these therapies. Consistently, recent clinical studies have highlighted VEGF-A splice variants as predictive biomarkers in response to bevacizumab. Hence, identification of the upstream signaling pathways that control VEGF-A pre-mRNA splicing, better characterization of the specific biological functions played by each VEGF-A splice variant, and analysis of the impact of anti-angiogenic therapies on VEGF-A pre-mRNA splicing are critical goals. The purpose of this chapter is to summarize the current knowledge in this field.