<p>Retinal ischemic perivascular lesions (RIPLs) are characteristic focal thinning of the inner nuclear layer, with an upward expansion of the outer nuclear layer identified by spectral domain optical coherence tomography (SD-OCT), causing a focal irregular appearance of the middle retina. RIPLs result from retinal hypoperfusion in the deep capillary plexus, as a legacy of paracentral acute middle maculopathy, representing permanent anatomical markers of prior ischemic events. Although frequently found incidentally during routine eye examinations, RIPLs may provide insights into subclinical vascular damage that underpins various cardio- and cerebrovascular diseases. The aim of this narrative review is to summarize the relationships of RIPLs with retinal and systemic vascular diseases, including arterial hypertension, coronary artery disease, carotid artery stenosis, atrial fibrillation, stroke, sickle cell disease, and diabetes mellitus. Cardiovascular and metabolic diseases, which are the leading causes of morbidity and mortality worldwide, often remain asymptomatic for years despite early structural changes until severe adverse events occur. Noninvasive retinal biomarkers such as RIPLs, which are readily and noninvasively detected through SD-OCT scans, could help in the early detection and stratification of patients at risk for cardiovascular diseases, facilitate timely medical interventions and lifestyle changes, and ultimately improve disease prevention in a “personalized medicine” approach. While further research is needed to establish the prevalence of RIPLs in the general population and their full clinical significance, advances in ophthalmic imaging technologies combined with rapid progress in artificial intelligence applications in medical research could accelerate the development of RIPLs in retinal imaging-based oculomics.</p>