Cell-to-cell communication is fundamental for embryo development and subsequent tissue homeostasis. This communication is often mediated by a small number of signaling pathways in which a secreted ligand binds to the surface of a target cell, thereby activating signal transduction. In vertebrate neural development, these signaling mechanisms are repeatedly used to obtain different and context-dependent outcomes. Part of the versatility of these communication mechanisms depends on their finely tuned regulation that controls timing, spatial localization, and duration of the signaling. The existence of secreted antagonists, which prevent ligand–receptor interaction, is an efficient mechanism to regulate some of these pathways. The Hedgehog family of signaling proteins, however, activates a pathway that is controlled largely by the positive or negative activity of membrane-bound proteins such as Cdon, Boc, Gas1, or Megalin/LRP2. In this review, we will use the development of the vertebrate retina, from its early specification to neurogenesis, to discuss whether there is an advantage to the use of such regulators, pointing to unresolved or controversial issues.