The world is entering a new era of exploring and exploiting the deep-underground space. With humans poised to reach historical depths in the use of the deep Earth, it is essential to understand the effect of the deep-underground environment on the health of humans and other living organisms. This article outlines the history and development of biological research conducted in deep-underground laboratories and provides insight into future areas of investigation. Many deep-underground laboratories have investigated the effects of reduced cosmic ray muons flux, searching for rare events such as proton decay, dark matter particles, or neutrino interactions, but few have focused on the influence of the environmental factors in the deep-underground on living organisms. Some studies revealed that prokaryote and eukaryote cells maintained in low levels of background radiation exhibited an stress response, which manifested as changes in cell growth, enzyme activity, and sensitivity to factors that cause genetic damage; however, the underlying mechanisms are unclear. There remains an urgent need to understand the detrimental and beneficial biological effects of low background radiation and other factors in the deep-underground on humans and other organisms. Consequently, a multidisciplinary approach to medical research in the deep-underground has been proposed, creating a new discipline, deep-underground medicine, and representing a historical milestone for exploring the deep Earth and in medical research.