The central noradrenergic system comprises multiple brainstem nuclei whose cells synthesize and release the catecholamine transmitter norepinephrine (NE). The largest of these nuclei is the pontine locus coeruleus (LC), which innervates the vast majority of the forebrain. NE interacts with a number of pre- and postsynaptically expressed G protein-coupled receptors to affect a wide array of functions, including sensory signal processing, waking and arousal, stress responsiveness, mood, attention, and memory. Given the myriad functions ascribed to the locus coeruleus-noradrenergic (LC-NE) system, it is unsurprising that it is implicated in many disease states, including various mood, cognitive, neuropsychiatric, and neurodegenerative diseases. The LC-NE system is also notably sexually dimorphic with regard to its morphologic and anatomical features as well as how it responds to the peptide transmitter corticotropin releasing hormone (CRH), a major mediator of the central stress response. The sex-biased morphology and signaling that is observed in the LC could then be considered a potential contributor to the differential prevalence of various diseases between men and women. This chapter summarizes the primary differences between the male and female LC, based primarily on preclinical observations and how these disparities may relate to differential diagnoses of several diseases between men and women.