In amyotrophic lateral sclerosis (ALS), an adult-onset progressive degeneration of motor neurons occurring as sporadic and familial disease, there is emerging evidence for and against the role of vascular endothelial growth factor (VEGF), an endothelial cell mitogen crucial for angiogenesis, in its etiopathogenesis. Our understanding of the role of VEGF in ALS has come from studies of both experimental models and human cases. In this article, I have examined in detail the in vitro and in vivo evidence for and against VEGF in ALS, concluding that more compelling evidence is required before we can conclusively link VEGF to ALS in humans.