A key process enabling the correct functioning of neural circuits involves the formation of multi‐layered membranous myelin sheaths around axons. Myelin sheaths, made by specialised glial cells called oligodendrocytes in the central nervous system (CNS), metabolically support underlying axons and speed up electrical impulse conduction, aiding efficient communication between neurons. As only a subset of axons in the CNS are myelinated, with unique patterns developed therein, it raises the questions: how does an oligodendrocyte choose which axon to myelinate and what regulates the amount of myelin made? The production of myelin sheaths by the oligodendrocyte, is under strong influence from of a range of signals including those mediated by G protein‐coupled receptor (GPR) superfamily members. One GPR, Endothelin receptor B (EDNRB), best known for regulating blood flow, had previously been demonstrated to both positively and negatively influence myelination. I have investigated how EDNRB regulates myelination using an in vitro myelination assay, alongside in vivo analysis in zebrafish and mice. These systems identified a direct signalling role for EDNRB in the promotion of myelin sheath number. Furthermore, profiling the protein signalling cascade downstream of this receptor identified a range of known and novel factors involved in the regulation of myelin sheath number including the MAPK pathway, Src family kinases, ErbB receptors, protein kinase C ε, NMDAR and AMPAR. Functional analyses of a subset of these factors elucidate how EDNRB signalling, potentially connecting signals from a range of cell types, ensures correct adequate myelination in the CNS.