Serious infection elicits inflammatory processes that act through a range of molecular pathways, including cytokine signaling. It is not established however that noradrenaline (NA), a widely distributed neurotransmitter in the brain that is also a principal output molecule of the sympathetic nervous system, can produce psychological effects associated with infection. This paper puts forth the hypothesis that through neural-immune crosstalk, serious infection increases noradrenergic signaling, both in the central nervous system and in peripheral organs. In this manner, elevated noradrenergic transmission may help produce basic symptoms of infection such as fever, fatigue, aches and pains (including headache), nausea, and loss of appetite. NA may also promote cognitive impairment, major depression, unipolar mania, and even epileptic seizures in some cases. The paper focuses on three major types of infection: influenza (viral), tuberculosis (bacterial), malaria (parasitic), while also summarizing the potential relationship between NA and human immunodeficiency virus (HIV) infection. Four lines of evidence are used to test association between NA and influenza, tuberculosis, and malaria: direct measures of NA and its metabolites; and incidence of hypertension, bipolar mania, and epileptic seizures, since the latter three conditions may be associated with elevated NA. In addition, heart rate variability data are examined with respect to a number of infectious diseases, since those data provide information on sympathetic nervous system activity. While the data do not unequivocally support elevated noradrenergic signaling promoting psychological symptomatology with infection, many studies are consistent with this view.Copyright © 2020 Elsevier Ltd. All rights reserved.