Compared to conventional neurons that use synaptic mechanisms to communicate with closely apposed targets, peptidergic neuroendocrine neurons release relatively large quantities of peptide into the vasculature to control neuroendocrine function at more distal sites. This means that maintaining adequate amounts of peptide for release through controlled biosynthesis is critical for their function. But the flexible and adaptive responses these neurons generate to many different challenges require synthesis and release must be coordinated in some way. How neuroendocrine—or in fact, any neuropeptide—neurons link appropriate levels of peptide biosynthesis with the patterns of action potentials that drive peptide release is unknown. Here we review possible mechanisms used by CRH neuroendocrine neurons in the paraventricular nucleus of the hypothalamus to achieve this coordination as they are driven by catecholaminergic inputs from the hindbrain. These particular inputs are essential for ACTH responses to glycemic challenges. We then compare this situation to the one seen across the day in the absence of stress when circulating ACTH and corticosterone exhibit predictable variations throughout the day. This activity pattern is driven by a completely different set of inputs. Based on these and other results, we propose that CRH synthesis and release mechanisms are not tightly and invariably linked together as CRH neurons are activated. Instead, complex coupling mechanisms exist both as a property of the pre-motor network that provides direct synaptic inputs to CRH neurons, and in the complex intracellular signal transduction mechanisms engaged by the very diverse set of receptors expressed by CRH neurons. This coupling process provides neuroendocrine CRH neurons with a versatile and dynamic mechanism that links peptide biosynthesis and release in an efficient and highly adaptable manner.