The paraventricular nucleus (PVN) of the hypothalamus has been described as the "autonomic master controller". It co-ordinates critical physiological responses through control of the hypothalamic-pituitary-adrenal (HPA)-axis, and by modulation of the sympathetic and parasympathetic branches of the central nervous system. The PVN comprises several anatomical subdivisions, including the parvocellular/ mediocellular subdivision, which contains neurones projecting to the medulla and spinal cord. Consensus indicates that output from spinally-projecting sympathetic pre-autonomic neurones (SPANs) increases blood pressure and heart rate, and dysfunction of these neurones has been directly linked to elevated sympathetic activity during heart failure. The influence of spinally-projecting SPANs on cardiovascular function high-lights their potential as targets for future therapeutic drug development. Recent studies have demonstrated pharmacological control of these spinally-projecting SPANs with glutamate, GABA, nitric oxide, neuroactive steroids and a number of neuropeptides (including angiotensin, substance P, and corticotrophin-releasing factor). The underlying mechanism of control appears to be a state of tonic inhibition by GABA, which is then strengthened or relieved by the action of other modulators. The physiological function of spinally-projecting SPANs has been subject to some debate, and they may be involved in physiological stress responses, blood volume regulation, glucose regulation, thermoregulation and/or circadian rhythms. This review describes the pharmacology of PVN spinally-projecting SPANs and discusses their likely roles in cardiovascular control.