Although hyperglycemia, high blood pressure and aging increase the risk of developing kidney complications, some diabetes patients exposed to these risk factors do not develop kidney disease, suggesting the presence of endogenous protective factors. There is a growing need to understand these factors determining protection of the kidney in order to improve the design of preventive strategies and to enhance the processes responsible for renoprotection. The aim of this review was to present the existing molecular and epidemiological data on factors showing protective effects in diabetic kidney disease, and to summarize the evidence regarding their potential in the area of future clinical diagnostics, therapeutics and early preventive strategies. These include transcriptomic and proteomic studies regarding the anti-inflammatory, anti-fibrotic and regenerative factors that were associated with slower progression of renal function loss. Another focus is the new evidence regarding the evaluation of alterations in the regulatory epigenome and its involvement in the risk of diabetic kidney disease. Further effort is required to validate and extend these findings, and to define their potential for clinical implementation in the future.