The sympathetic adjustments triggered by acute mild hypoxia (sympathetic chemoreflex) are initiated by activation of peripheral chemoreceptors whereas more severe hypoxia activates the sympathetic outflow via direct effects on the brainstem. In both cases the rostral ventrolateral medulla (RVLM) plays a critical role in these responses. The first part of this review briefly describes the general input-output properties of the presympathetic neurons of RVLM before focusing on the neural pathways leading to their excitation in response to peripheral chemoreceptor stimulation. The extent to which the central respiratory network contributes to the sympathetic chemoreflex is then discussed before briefly alluding to its role in obstructive sleep apnea and other pathologies. The second half of the review examines the direct effects of hypoxia on RVLM neurons and whether this region and the presympathetic neurons in particular qualify as a physiological central oxygen sensor. The literature is also examined in the context of cerebral ischemia, the Cushing response and the genesis of certain forms of hypertension.