Diabetes mellitus and its complications have become one of the most important health problems in the world. Nowadays, diabetic nephropathy is the main cause of end-stage renal failure and need for renal substitutive therapy. The exact mechanisms leading to the development and progression of renal damage in diabetes are not yet completely known. Growing evidence indicates that activation of innate immunity with the development of a chronic low-grade inflammatory response is a recognized factor in the pathogenesis of this disease. Inflammatory molecules and pathways, including metabolic routes, oxidative stress, growth factors, chemokines, adhesion molecules and inflammatory cytokines, interact in manifold ways leading to renal injury responsible for the development and progression of this complication. The increasing knowledge and understanding of the role of these inflammatory mechanisms, with an integrative comprehension of this network, will facilitate the identification of new therapeutic targets and the development of new strategies that can be translated successfully into clinical applications.