The plasma soluble melanins (PSM) form spontaneously in vitro and in vivo and their formation involves oxidative polymerization and copolymerization of dopa, catecholamines, homogentisic acid, 3-hydroxyanthranilic acid, p-aminophenol, p-phenylenediamine, and other end(ex)ogenous ortho and para polyhydroxy-, (poly)hydroxy(poly)amino- and polyamino-phenyl compounds. The build up of PSM is visible within 2–3 h after the start of incubation at 37°C with 1 mg/ml of plasma. PSM also form similarly in blood and these processes cause hemolysis. The mean quantity of PSM in normal human plasma is 1.61±0.1 (S.D.) mg/ml ( n=20) and in normal human urine is 1.1±1.2 g/24 h collection ( n=8). They contribute to the yellow color of plasma and urine. Antioxidants delay the formation of PSM. The deposited melanins also form from these precursors. Reactive oxygen side products (ROSP) are generated during and after melanogenesis. Melanins in vivo are generally associated with proteins or with proteins and lipids. The PSM–protein–lipid complexes are called plasma soluble lipofuscins (PSL), because they have histochemical and fluorescence properties similar to those of solid lipofuscins. The soluble and deposited melanins (SDM) and their intermediates have similar toxic chemical reactivities. The oxidizing quinoid (they can produce partially and completely substituted conjugates) and the semiquinoid free radical intermediates are also moieties in most human melanin structures. Soluble melanins formed from dopa, or dopamine, or norepinephrine in weak alkaline solution have been shown to be toxic to human CD4+ lymphoblastic cells (MT-2) at higher than 10 μg/ml concentrations. Alkaptonuria with high levels of homogentisic acid in the plasma is a potentially fatal disease, exhibiting the toxic effects of the homogentisic acid melanin (soluble and deposited), its intermediates and the ROSP. Patients with alkaptonuria develop arthritis and often suffer from other diseases too, including cardiovascular disease (frequent cause of death) and kidney disease. Pheochromocytoma, with high levels of catecholamines in the plasma is another potentially fatal disease. The catecholamine PSM of pheochromocytoma have very light yellow or practically no colors, due to the concentrations and chemical structures. Pheochromocytomas can cause hypertension, cardiovascular disease (frequent cause of death), kidney disease, stroke, cancer, amyloid formation and can mimic many other diseases, including acute pancreatitis, carcinoid, neuroblastoma, psychiatric illness, hypercalcemia, retinal vascular lesions, and diabetes mellitus. Pheochromocytoma is potentially fatal even in patients without hypertension. Following trauma and surgery, heavily pigmented eyes are apt to experience greater inflammation than lightly pigmented eyes. In Parkinson’s disease those neurons are lost first in the substantia nigra and locus ceruleus which contain the greatest amounts of neuromelanins. The antihypertensive alphamethyldopa causes Parkinson’s syndrome. It forms PSM in a short time in vitro. The side effects of l-dopa (immobility episodes alternate with normal or involuntary movements; psychotic abnormalities) suggest that the SDM, their intermediates and the ROSP present naturally in vivo are involved in the cause of Parkinson’s disease and Alzheimer’s disease. There is a large overlap between these two diseases. Melanins are stable free radicals, redox-polymers, highly reactive chemically and the different melanins have similar toxic chemical reactivities, therefore it is likely that the SDM, their intermediates and the ROSP present naturally in vivo, without sufficient systemic and local antioxidation protection, are implicated in the cause of accelerated normal aging (they are a continuous source of assault to the tissues and vital biochemicals) and in the development of a wide variety of disease processes, including arthritis, primary hypertension, cardiovascular disease, carcinogenicity, chronic kidney disease, diabetes mellitus, Parkinson’s disease and Alzheimer’s disease. Furthermore the SDM, their intermediates and the ROSP seem to contribute to the etiologic factors that link a dominant disease to other diseases, e.g. primary hypertension to kidney failure, stroke and coronary heart disease or rheumatoid arthritis to anemia, amyloidosis, cardiovascular disease and kidney disease; and the structure–activity relationships of these chemicals and the lack of systemic and local antioxidation protections seem to determine which disease dominates. The solid eu-, pheo-, mixed-type- and neuromelanins are formed and located in the cells, therefore they can not damage the extracellular environment. Increased rates of oxidant formation can be toxic to many tissues that have adequate antioxidant defences only against normal rates of oxidant formation. On the other hand normal rates of oxidant generation can be toxic to tissues with abnormally low antioxidant protection. The presence of oxidative stress in most or perhaps all diseases has been stated by several authors.