Abstract: The neuromodulatory peptide somatostatin (somatotropin release inhibiting factor, SRIF)-14 acts at multiple levels through five SRIF receptor subtypes (sst1 to sst5). SRIF-28 is also derived from a common propeptide translated from a single SRIF gene, although SRIF-14 is the predominant form in the mammalian nervous system. Due to its short half-life, synthetic SRIF analogs have been developed over the years and are available for therapeutic approaches. In particular, sandostatin (which contains octreotide) lanreotide and pasireotide are currently available in an injectable formulation. These analogs, alone or in combination with other agents (also as preoperative treatment), are used in clinical practice in endocrinological indications, i.e. acromegaly, Cushing’s disease, thyrotropinomas and gastroenteropancreatic neuroendocrine tumors, and in gastrointestinal indications, i.e. complications after pancreatic surgery and gastroesophageal varices in patients with cirrhosis (Gomes-Porras et al., 2020). The variable success rate of the administration of SRIF analogs depends on the particular aspects related to the pathology and the expression of sst1-sst5 at the cellular and tissue level, since the type and the amount of receptors are crucial factors for the drug response. Of interest, SRIF analogs represent an off-label treatment option in several conditions in the field of endocrinology, oncology, digestive, general surgery and ophthalmology, including diabetic retinopathy (DR)/diabetic macular edema and Graves’ orbitopathy. Indeed, SRIF analogs with potent neuroprotective properties are highly effective in protecting retinal cells from a variety of insults (Cammalleri et al., 2019). Since primary damage to retinal ganglion cells (RGCs) has been recognized as a major pathological feature in a number of vision-threatening diseases, this Perspective article will focus on recent preclinical evidence regarding the neuroprotective role of the SRIF system in RGCs. In particular, specific novel aspects related to the promising application of SRIF analogs in retinal neurodegeneration induced by metabolic insults will be discussed.