Docosahexaenoic acid (22:6n-3) esterified into phospholipids represents by far the most prevalent fatty acid of rod photoreceptor disc membranes and synaptic terminals. During synaptogenesis and photoreceptor biogenesis, plasma lipoproteins, secreted mainly by the liver, are the main source of plasma 22:6n-3 for the central nervous system. This systemic route (the long loop) also operates in mature animals for morphogenesis and maintenance of excitable membranes (e.g., during constant renewal of photoreceptor disc membranes). When radiolabeled 18:3n-3, the dietary precursor of 22:6n-3, is systemically supplied to 3-day-old mouse pups, it is elongated and desaturated in the liver, leading to the synthesis of 22:6n-3-lipoproteins that shuttle the fatty acid through the bloodstream to retina and brain. When radiolabeled 22:6n-3 was used, a more efficient labeling of brain and retinal lipids was achieved. The retinal pigment epithelium is involved, not only in the uptake of 22:6n-3 from circulating lipoproteins in the choriocapillaris but also in the recycling of 22:6n-3 from degraded phagosomal phospholipids back to the inner segments of photoreceptors (the short loop), following each phagocytic event. An interplay among efficient 22:6n-6 delivery from the liver, selective uptake by retinal pigment epithelium photoreceptor cells, and avid retinal retention may contribute to the enrichment of excitable membranes of the retina with 22:6n-3-phospholipids.