Diabetes is one of the major challenges of modern medicine, as it is considered a global epidemic of the XXI century. The disease often leads to the development of serious, health threatening complications. Diabetic foot syndrome is a characteristic set of anatomical and molecular changes. At the macroscopic level, major symptoms are neuropathy, ischemia and chronic ulceration of the lower limb. In every third patient, the neuropathy develops into Charcot neuroarthropathy characterized by bone and joints deformation. Interestingly, all these complications are a result of impaired healing processes and are characteristic for diabetes. The specificity of these symptoms comes from impaired molecular mechanisms observed in type 1 and type 2 diabetes. Decreased wound and fracture healing reflect gene expression, cellular response, cell functioning and general metabolism. Here we present a comprehensive literature update on the molecular factors contributing to diabetic foot syndrome.