Acute kidney injury is an increasingly common global health problem and is associated with severe morbidity and mortality. In addition to facing high mortality rates, the survivors of acute kidney injury are at increased risk of developing chronic kidney disease and end-stage renal disease. Renal ischemia-reperfusion injury (IRI) is the most common cause of acute kidney injury, and results from impaired delivery of oxygen and nutrients to the kidney. Massive leukocyte influx into the post-ischemic kidney is one of the hallmarks of IRI. The recruited leukocytes exacerbate tissue damage and, if uncontrolled, initiate the progressive changes that lead to renal fibrosis and chronic kidney disease. Early on, recruitment and activation of platelets promotes microthrombosis in the injured kidney, further exacerbating kidney damage. The diversity, complexity, and multiplicity of pathways involved in leukocyte recruitment and platelet activation make it extremely challenging to control these processes, and past efforts have met with limited success in human trials. A generalized strategy to inhibit infiltration of inflammatory leukocytes and platelets, thereby reducing inflammation and injury, may prove to be more beneficial. In this review, we summarize recent findings demonstrating that the neuronal guidance cues, Slit and Roundabout (Robo), prevent the migration of multiple leukocyte subsets towards diverse inflammatory chemoattractants, and have potent anti-platelet functions in vitro and in vivo. These properties uniquely position Slit2 as a novel therapeutic that could be used to prevent acute kidney injury associated with IRI.