Tissue injury in diabetes results from cell damage and death, impaired communication among cells, dysfunction of nerves and blood vessels, and detrimental responses to systemic signals, such as inflammation. The development of the clinical manifestations depends on tissue-specific responses to injury and impairments in repair and regenerative processes. The knowledge base of the pathologic process in different tissues varies considerably, but in all organ systems a better understanding of the mechanisms is needed. How does systemic inflammation from dysregulation of the innate and adaptive immune systems affect the kidney? What are the mechanisms of injury in specialized cells, such as podocytes or tubular epithelial cells? What kidney disease is associated with diabetes from non-diabetes related forms of these diseases? Does diabetes accelerate the same pathologic processes or have unique components? What mechanisms are responsible for the increased mortality in people with diabetes and end-stage renal failure? Will aggressive treatment to normalize the blood sugar prevent this progression? Is there a point in the progression of diabetes complications when the pathologic process becomes relatively independent of the diabetes-related factors that initiate it? Is there a point when the progression becomes irreversible?