As the growing population of individuals residing or working in deep underground spaces for prolonged periods, it has become imperative to understand the influence of factors in the deep underground environment (DUGE) on living systems. Heping Xie has conceptualized the concept of deep underground medicine to identify factors in the DUGE that can have either detrimental or beneficial effects on human health. Over the past few years, an increasing number of studies have explored the molecular mechanisms that underlie the biological impacts of factors in the DUGE on model organisms and humans. Here, we present a summary of the present landscape of biological and medical research conducted in deep underground laboratories and propose promising avenues for future investigations in this field. Most research demonstrates that low background radiation can trigger a stress response and affect the growth, organelles, oxidative stress, defense capacity, and metabolism of cells. Studies show that residing and/or working in the DUGE has detrimental effects on human health. Employees working in deep mines suffer from intense discomfort caused by high temperature and humidity, which increase with depth, and experience fatigue and sleep disturbance. The negative impacts of the DUGE on human health may be induced by changes in the metabolism of specific amino acids; however, the cellular pathways remain to be elucidated. Biological and medical research must continue in deep underground laboratories and mines to guarantee the safe probing of uncharted depths as humans utilize the deep underground space.