Distal symmetric sensorimotor polyneuropathy (DSPN) is the most common neurological manifestation in diabetes. Major risk factors of DSPN include diabetes duration, hyperglycemia, and age, followed by prediabetes, hypertension, dyslipidemia, and obesity. Height, smoking, insulin resistance, hypoinsulinemia, and others represent an additional risk. Importantly, hyperglycemia, hypertension, dyslipidemia, obesity, and smoking are modifiable. Stringent glycemic control has been shown to be effective in type 1, but not to the same extent in type 2 diabetes. Antilipidemic treatment, especially with fenofibrate, and multi-factorial intervention have produced encouraging results, but more experience is necessary. The major comorbidities of DSPN are depression, autonomic neuropathy, peripheral artery disease, cardiovascular disease, nephropathy, retinopathy, and medial arterial calcification. Knowledge of risk factors and comorbidities has the potential to enrich the therapeutic strategy in clinical practice as part of the overall medical care for patients with neuropathy. This article provides an updated overview of DSPN risk factors and comorbidities.