Epidermal squamous cell carcinoma is among the most common cancers. These tumors are comprised of phenotypically diverse populations of cells that display varying potential for proliferation and differentiation. An important goal is identifying cells from this population that drive tumor formation, in order to therapeutically target and eliminate this population of cells. To enrich for tumor-forming cells, cancer cells were grown as spheroids in non-attached conditions. Detailed analysis reveals that spheroid-selected cultures are highly enriched for expression of epidermal stem cell and embryonic stem cell markers, including ALDH1, keratin 15, CD200, and keratin 19. This limited subpopulation of epidermal cancer stem cells (ECS cells), in squamous cell carcinoma, form rapidly growing, invasive and highly vascularized tumors, as compared with non stem cancer cells. We show that ECS cell-produced vascular endothelial growth factor (VEGF)-A is required for the maintenance of this phenotype, as knockdown of VEGF-A gene expression or treatment with VEGF-A inactivating antibody reduces these responses. Surprisingly, the classical mechanism of VEGF-A action via interaction with VEGF receptors does not mediate these events, as these cells lack VEGFR1 and VEGFR2. Instead, VEGF-A acts via the Neuropilin-1 (NRP-1) co-receptor to trigger intracellular events leading to ECS cell survival and formation of aggressive, invasive and highly vascularized tumors. We further identify a novel signaling cascade downstream of this VEGF-A/NRP-1 interaction that shows NRP-1 forms a complex with GIPC1 and α6/4-integrin to activate FAK/Src signaling which leads to stabilization of a YAP1/∆Np63α to enhance ECS cell survival, invasion and angiogenesis.