More than 60 years ago, Geoffrey Harris described his "neurohumoral theory," in which the regulation of pituitary hormone secretion was a "simple" hierarchal relationship, with the hypothalamus as the controller. In models based on this theory, the electrical activity of hypothalamic neurons determines the release of hypophysiotropic hormones into the portal circulation, and the pituitary simply responds with secretion of a pulse of hormone into the bloodstream. The development of methodologies allowing the monitoring of the activities of members of the hypothalamic-vascular-pituitary unit is increasingly allowing dissection of the mechanisms generating hypothalamic and pituitary pulses. These have revealed that whereas hypothalamic input is required, its role as a driver of pulsatile pituitary hormone secretion varies between pituitary axes. The organization of pituitary cells has a key role in the modification of their response to hypophysiotropic factors that can lead to a memory of previous demand and enhanced function. Feedback can lead to oscillatory hormone output that is independent of pulses of hypophysiotropic factors and instead, results from the temporal relationship between pituitary output and target organ response. Thus, the mechanisms underlying the generation of pulses cannot be generalized, and the circularity of feedforward and feedback interactions must be considered to understand both normal physiological function and pathology. We describe some examples of the clinical implications of recognizing the importance of the pituitary and target organs in pulse generation and suggest avenues for future research in both the short and long term.