About 400 subglacial lakes are known from Antarctica. The question of whether life unique of subglacial lakes exists has been paramount since their discovery. Despite frequent evidence of microbial life mostly from accretion ice, subglacial lakes are characterized by physiologically hostile conditions to metazoan life, as we know it. Pure water (salinity ≤0.4–1.2%), extreme cold (−3°C), high hydrostatic pressure, areas of limited or no oxygen availability and permanent darkness altogether require physiological adaptations to these harsh conditions. The record of gene sequences including some associated with hydrothermal vents does foster the idea of metazoan life in Lake Vostok. Here, we synthesize the physico-chemical environment surrounding sub-glacial lakes and potential sites of hydrothermal activity and advocate that the physico-chemical stability found at these sites may be the most likely sites for metazoan life to exist. The unique conditions presented by Lake Vostok may also offer an outlook on life to be expected in extra-terrestrial subglacial environments, such as on Jupiter's moon Europa or Saturn's moon Enceladus.