The trigeminal ganglion plays a key role in primary headache pathophysiology. Calcitonin gene-related peptide (CGRP) and CGRP receptors are expressed in trigeminal neurons that form C-fibers and A-fibers, respectively. In acute migraine and cluster headache attacks, there is release of CGRP into the cranial venous outflow. In addition, intravenous CGRP can induce migraine-like symptoms in migraine patients. These findings led to the development of anti-migraine therapies that inhibit CGRP action. Currently, CGRP receptor antagonists, the gepants, and monoclonal antibodies towards CGRP and the CGRP receptor are all showing positive relief of acute and chronic migraine in clinical trials. However, there is still much to learn about the role of CGRP and CGRP receptors in headache pathophysiology, the critical anatomical sites, peripheral or central, of anti-CGRP agents, and the potential involvement of CGRP-related peptides and receptors. This review provides a brief history of the discovery of the role of CGRP in migraine and highlights current progress in understanding the complexity of the trigeminovascular pathway and its peptide transmitters.