Acute kidney injury (AKI) is a severe complication of critically ill patients, characterized by high morbidity and mortality and affecting both short and long term. High mortality rate in AKI patients is usually associated with the onset of multiorgan dysfunction syndrome, characterized by a link between kidney and other organ impairments, including heart, lung, liver, and brain. Several molecular mechanisms of organ crosstalk have been proposed in the last years, exploring the potential role of immune response, changes in hemodynamics and fluid balance, oxidative stress, and hormone regulation. This chapter provides the recent findings of molecular pathways involved in organ crosstalk in AKI patients, highlighting the potential implications in AKI treatment.