Despite its apparently simple molecular aetiology, sickle cell disease (SCD) has long been known to have a remarkably variable clinical course, with complications involving many organs including the kidneys. Whilst many affected individuals show no evidence of renal involvement into late adulthood, others develop renal dysfunction in childhood or early adult life with a significant proportion eventually requiring renal replacement therapy. This review explores the pathophysiology and clinical manifestations of sickle cell nephropathy (SCN) and discusses how each complication can be investigated, monitored and managed in the outpatient setting. We summarize current knowledge of genetic modulation of sickle-related renal dysfunction. We outline the evidence for various treatment options and discuss others for which little evidence currently exists.