Neuropilin-1 (Nrp1) and/or neuropilin-2 (Nrp2) are expressed by many tumors, correlating with a poor prognosis. Normally, Nrp1 is expressed by neurons, endothelial cells, dendritic cells (DCs) and Treg cells, while Nrp2 has a more limited distribution. Because neuropilins are coreceptors for VEGF, it has been thought they stimulate tumor angiogenesis, but they may also act otherwise. We recently reported that Nrp1 binds and activates LAP-TGF-beta1 (the latent form) and enhances Treg activity. Here, we report that both Nrp1 and Nrp2 interact with TGF-beta1, as well as TGF-beta receptor components, and induce internalization of the TGF-beta receptor complex. This enhances signaling by the Smad pathway. In accord with this, we found that both Nrp1 and Nrp2 activate latent TGF-beta1 on the membrane of breast cancer cells. The classical TGF-beta receptors (RI, RII and RIII) only bind active TGF-beta, but our data suggest that the neuropilins allow responsiveness to latent TGF-beta by its activation. We also find that TGF-beta competes with VEGF for binding to Nrp1/Nrp2, possibly altering angiogenesis. TGF-beta has been linked to metastasis and, thus, the neuropilins may promote metastasis by capturing and activating latent TGF-beta. Our novel findings are relevant to cancer biology, immune regulation and angiogenesis. This work was funded by the Ontario Institute for Cancer Research, Province of Ontario, Canada.