The TGFβ family member Nodal is essential during development to allocate pluripotent cells to distinct germ layers and to establish the basic body plan. To establish a signaling gradient of the transcription factors Smad2 and Smad3, Nodal forms a complex with Activin receptors that is activated with the help of the glycosylphosphosphatidyl-inositol-anchored proteoglycans Cripto or Cryptic. To elucidate the underlying mechanism, we investigated whether Cripto regulates the proteolytic maturation and/or trafficking of Nodal precursor protein. We show that Cripto captures Nodal already during secretion, partly via the propeptide, and assembles a processing complex with the proprotein convertases Furin at the cell surface. Subsequently, Cripto mediates uptake of mature Nodal via a conclathrin, noncaveolar pathway to signaling endosomes. Our results suggest that Cripto is a receptor for proprotein convertases and couples Nodal processing and signaling in target cells.