In 1998, George Vande Woude's lab discovered that anthrax lethal factor (LF), the principal virulence component of anthrax toxin, was a zinc-metalloprotease that cleaved and inactivated mitogen-activated protein kinase kinases (MKK). It was perhaps not surprising, given the known roles of MKK1 and 2 in cell proliferation, that LF was subsequently found to dramatically inhibit tumor growth in vivo. What was not anticipated, however, was that the tumors treated with LF would have a substantially reduced vascular content. This intriguing result was one of the first indications that MKK signaling plays an important role in promoting tumor vascularization in vivo. In the following short review, we will compare in vitro and in vivo evidence that supports the hypothesis that MKK signaling pathways are essential for vascularization.