G protein-coupled receptors (GPCRs) have emerged as incredibly successful drug targets. Members of the adhesion GPCRs (aGPCR) family are characterized by diverse extracellular regions (ECRs), which play roles in cell adhesion, and mediate a subset of aGPCR functions in vivo. Though these receptors are implicated in myriad disease processes, there are no aGPCR-targeted therapeutics to date, due in large part to both the absence of well-behaving ligands as well as the technical challenges associated with mechanistic studies of aGPCR ECRs. We present a structural and functional study of the aGPCR GPR56/ADGRG1, a receptor critical for neurodevelopment and leukemia progression. To overcome many of the challenges mentioned above, we generated over thirty synthetic protein ligands, termed monobodies, that bind diverse epitopes across the ECR. Using a monobody crystallization chaperone, we solved the structure of the full ECR of GPR56, a first for any aGPCR, revealing the domain boundaries in the ECR as well as the identity and unique fold of the previously undefined N-terminal domain. We showed this domain regulates signaling and natural ligand binding in vitro, is deleted via alternative splicing, and mediates myelination in vivo. Additionally, we developed monobodies with stimulatory and inhibitory functions, demonstrating that ECR-targeted ligands can directly regulate aGPCR signaling, and are therefore valuable experimental reagents as well as lead-molecules for therapeutic development. Our results suggest an intricate, ECR-mediated molecular mechanism underlying aGPCR regulation. With the ultimate goal of combating aGPCR-mediated diseases, our findings will pave the way for targeted therapeutic development.