Acute kidney injury (AKI) contributes significantly to morbidity and mortality in both adults and children. While clinical data suggest that AKI contributes to and exacerbates multiorgan failure, the physiologic and molecular mechanisms responsible for these interactions were previously unknown. New data linking AKI with distant-organ dysfunction includes evidence that inflammatory cascades are abnormal after organ injury. Leukocyte trafficking, cytokine expression, cell adhesion-molecule expression and membrane ion and water-channel expression in distant organs are deranged after kidney injury. The responses to oxidative stress after AKI are also altered, suggesting complex mechanisms of crosstalk between the injured kidney and distant organs. Novel methodologies, including genomics and proteomics, are now being employed to unravel interorgan communication to accelerate clinically meaningful discovery for this serious disease.