Cognitive function is an important and relatively understudied outcome of critical illness. Evidence suggests that neurotransmitter abnormalities and occult diffuse brain injury are important pathophysiologic mechanisms that underlie critical illness-associated CD. Markers that could be used to evaluate the influence of these mechanisms in individual patients include the following: SAA, certain brain proteins (S-100β, NSE, and MPB), and MRI tissue sodium concentration. Although recent advances in this area are exciting, they are still too immature to influence patient care. Additional research is needed if we are to understand better the relative contributions of specific mechanisms to the development of critical illness-associated cognitive dysfunction and to determine whether these mechanisms might be amenable to treatment or prevention.