Actual or potentially threatening stimuli in the external environment (i.e., psychological stressors) trigger highly coordinated defensive behavioral responses that are accompanied by appropriate autonomic and respiratory changes. As discussed in this review, several brain regions and pathways have major roles in subserving the cardiovascular and respiratory responses to threatening stimuli, which may vary from relatively mild acute arousing stimuli to more prolonged life-threatening stimuli. One key region is the dorsomedial hypothalamus, which receives inputs from the cortex, amygdala, and other forebrain regions and which is critical for generating autonomic, respiratory, and neuroendocrine responses to psychological stressors. Recent studies suggest that the dorsomedial hypothalamus also receives an input from the dorsolateral column in the midbrain periaqueductal gray, which is another key region involved in the integration of stress-evoked cardiorespiratory responses. In addition, it has recently been shown that neurons in the midbrain colliculi can generate highly synchronized autonomic, respiratory, and somatomotor responses to visual, auditory, and somatosensory inputs. These collicular neurons may be part of a subcortical defense system that also includes the basal ganglia and which is well adapted to responding to threats that require an immediate stereotyped response that does not involve the cortex. The basal ganglia/colliculi system is phylogenetically ancient. In contrast, the defense system that includes the dorsomedial hypothalamus and cortex evolved at a later time, and appears to be better adapted to generating appropriate responses to more sustained threatening stimuli that involve cognitive appraisal. defensive behavior; sympathetic activity; respiratory activity; hypothalamus; midbrain; sympathetic premotor nuclei AN ANIMAL'S SURVIVAL is dependent on being able to respond appropriately to stressors, which can be categorized into two different groups: interoceptive (also-called physical) stressors and exteroceptive (also-called psychological) stressors (44,133). Physical stressors are those that directly threaten homeostasis, such as hypoxia, hemorrhage, or infection, whereas psychological stressors can be defined as actual or perceived threats in the external environment. Psychological stressors can be further subdivided into conditioned stressors (i.e., ones that are normally innocuous but which are perceived as threatening because of previous experiences) or unconditioned stressors (i.e., ones that are intrinsically threatening, such as the sight, sound, or odor of a predator). Physical and psychological stressors activate different populations of neurons in the brain (44,63,102). Similarly, there is evidence that the autonomic responses to conditioned and unconditioned psychological stressors are also mediated by different pathways in the brain (62). In this review, which is based on my 2013 Carl Ludwig Distinguished Lecture to the American Physiological Society, I consider the brain mec...