Between 60% and 100% of patients with uremia have signs and symptoms of uremic neuropathy. Uremia can lead to the accumulation of guanidino compounds, creatine, creatol, methylglyoxal, guanidine, potassium and hyperparathyroidism, all of which are potentially nephrotoxic. Cross talk between the kidney and brain via anatomic, vasoregulatory, humoral and non humoral bi-directional pathways, uremia triggers the development of central and peripheral nervous system disturbances. Uremic encephalopathy, seizures, stroke, movement disorders, visual deterioration, impaired cognitive function and sleep disorders manifest centrally while polyneuropathy and carpal tunnel syndrome is commonly seen in the periphery. Chronic hemodialysis, peritoneal dialysis and renal transplant are definitive treatment options for uremia. Relatively novel therapies such as zinc, retigabine, flumarizine, alpha-lipoic acid, gangliosides, and benfotiamine help to mitigate or improve the symptoms by various mechanisms. This chapter will examine the specific mechanisms of injury caused by the nephrotoxic compounds mentioned above; then review the current literature on mechanism-specific interventions.