It has now been established that persons with higher resting heart rates are at increased risk of morbidity and mortality from a plethora of mental and physical illnesses. However, the mechanism underlying the predictive value of this core vital sign remains obscure. This seminal report will integrate clinical, neuropsychological, physiological, and genetic evidence to assert that an inherent hyperexcitability of the neurological system is at the heart of the connection between resting heart rate and disease. Hypothetically, neuronal hyperexcitability can cause multiple circuits in the brain to overfire, including cognitive circuits, limbic circuits, and autonomic circuits, thereby dysregulating the associated systems of the body and allowing the aberration to be detected through standard vital signs and related measures of autonomic activity. Because the cognitive-emotional system is exquisitely sensitive to neuronal excitation, the aberration could also manifest as psychiatric symptomatology, thus suggesting that psychiatric symptoms may be the first subjective markers of the abnormality. Based on the well-recognized link between mental illness, autonomic dysregulation, and systemic disease together with mounting evidence that the related illnesses are associated with gene variants whose protein products fail to adequately regulate the firing of neurons, the vulnerability trait could aptly be called Familial Limbic Autonomic System Hyperexcitability or “FLASH.” Because the trait appears to be so common, its effects so pervasive, and its expression so modifiable, its identification is of critical importance to every medical specialty. FLASH could give clinicians the first comprehensive biological target through which to treat and prevent a plethora of mental, emotional, and physical illnesses.