Recent research has unveiled an intricate and dynamic relationship between the gut and the kidney, the so-called gut-kidney crosstalk. Different gut microbiome compositions have been associated with acute kidney injury (AKI) and its progression. Dysbiosis disrupts physical, immune, and biological intestinal barriers, which may promote and potentiate the development of AKI. Conversely, during AKI, the clearance of inflammatory mediators and metabolic products decreases, leading to further gut injury and a vicious cycle. This deleterious crosstalk may be a potential target for therapeutic interventions. This chapter reviews the mechanisms, molecular mediators, and clinical implications of this bidirectional communication, shedding light on how these organs influence each other’s health and function.