Over 2.6 million adults over the age of 65 develop delirium each year in the United States (US). Delirium is associated with a significant increase in mortality and the US health care costs associated with delirium are estimated at over $164 billion annually. Despite the prevalence of the condition, the molecular pathophysiology of delirium remains unexplained, limiting the development of pharmacotherapies. Delirious patients can be identified by prominent impairments in attention and working memory (WM), two cognitive domains that localize to the dorsolateral prefrontal cortex (dlPFC). The dlPFC is also a key site for Alzheimer's disease (AD) pathology, and given the high risk of delirium in AD patients, suggests that efforts at understanding delirium might focus on the dlPFC as a final common endpoint for cognitive changes. Preclinical studies of the dlPFC reproduce many of the pharmacological observations made of delirious patients, including sensitivity to anticholinergics and an 'inverted U' pattern of dependence on monoaminergic input, with diminished performance outside a narrow range of signaling. Medications like guanfacine, which influence the dlPFC in the context of attention-deficit/hyperactivity disorder (ADHD), have emerged as therapies for delirium and motivate a detailed understanding of the influence of α-2 agonists on WM. In this review, I will discuss the neural circuitry and molecular mechanisms underlying WM and the function of the dlPFC. Localizing the cognitive deficits that are commonly seen in delirious patients may help identify new molecular targets for this highly prevalent disease.