Since the exact development of posterior subcapsular cataracts (PSCs) is poorly understood, we review various risk factors and propose a two-stage etiology for PSCs. The biological mechanisms associated with age-related cataracts (primarily nuclear cataracts, cortical cataracts and PSCs) were reviewed in relation to selected risk factors that induce PSCs (including atopy, diabetes, hypoparathyroidism, myopia, retinitis, solar radiation, steroid use, uveitis, vitrectomy and ionizing radiation). We particularly focused on ionizing radiation, as this is known to be a risk factor specific to PSCs. Based on an analysis of the reviewed material, we propose a detailed explanation of the etiology of PSCs. Lens epithelial cells (LECs) and lens fiber cells are normally hypoxic and therefore very sensitive to changes in oxidative stress, as quantified by the radiation oxygen effect. We hypothesize that the development of PSC opacities is a two-stage process. Stage I, early in life, is driven by risk factors that promote oxidative stress and ion-pump disruption, harming lens fibers and causing aberrant LECs to proliferate and ectopically migrate as Wedl cells (perhaps by processes associated with an epithelial to mesenchymal transition) to the posterior pole region. After a latent period, in Stage II the development of PSCs advances mainly due to chronic inflammation and other premature aging-related mechanisms that promote mature vacuolar or plaque PSC. This two-stage hypothesis of PSC etiology accounts for risk factors, such as aging, diabetes and ionizing radiation, which directly affects LECs and the lens. In addition, these risk factors can damage other ocular regions, such as the retina and vitreous, that also indirectly contribute to the development of PSCs. It is possible that the incidence of PSCs may be reduced by reversing the effects of Stage I through various means, including ocular antioxidants.

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