Ocular surface complications are prevalent in diabetes. For example, up to 54% of persons with diabetes have some form of dry eye disease (DED) and others have decreased corneal sensitivity and delayed epithelial wound healing. Although not life-threatening, these complications can be painful and lead to loss of work productivity, increased healthcare costs, and distorted vision or loss of vision. DED is classified as being either aqueous deficient or evaporative in nature, with the latter form related to environmental conditions such as heat, smoking, low humidity, and the former condition being attributed to Type 1 diabetes (T1D). DED can develop in animal models of T1D without surgical intervention or exogenous drugs and is a naturally occurring complication of hyperglycemia. Investigations have associated the onset of DED in T1D with the dysregulation of the Opioid Growth Factor (OGF) – OGF receptor (OGFr) regulatory pathway with upregulation of the peptide and receptor. This regulatory pathway is a tonically active, inhibitory pathway that is an important regulator during homeostasis and re-epithelialization, and plays a role in the onset and progression of autoimmune diseases. Blockade of the pathway using the opioid receptor antagonist naltrexone (NTX) rapidly reverses dry eye and corneal surface insensitivity in male and female rats with T1D within 5 days. This review focuses on our investigations of mechanisms related to the rapid reversal of diabetic DED and decreased corneal sensitivity following topical administration of NTX.