Mammalian spermatogenesis is a complex physiological process that takes place inside seminiferous tubules in the testis. This process involves a fine balance between cell proliferation, differentiation and apoptosis, ending up with a motile spermatozoon. In most mammals the testes are kept 4-5 °C below body core temperature in the scrotum and the spermatogenic process proceeds with a blood and oxygen supply that appears to be fairly independent of changes in other vascular beds in the body. Despite this well-controlled environment, special circumstances (i.e. genetics), lifestyle, occupational work, pathologies (e.g. diabetes, cryptorchidism and varicocele) and environmental exposure to low oxygen (hypoxia) can result in a decrease of blood flow, nutrients and oxygen supply along with increased temperature. All of these conditions, besides those that cause some pathological conditions, may lead to subfertility or infertility. However, they also represent unique conditions that help us to address some crucial questions about the cell biology and physiology of spermatogenesis: what advantage is there for the spermatogenic cell processes mentioned above taking place under mild hypothermia? What are the molecular and physiological processes that make spermatocytes especially vulnerable to high temperatures? What mechanisms of adaptation take place in the seminiferous tubules cells under hypoxia? What mechanisms lead to a decreased sperm output from spermatogenesis under hypoxia? Do these conditions have similar physiological and molecular pathways? In this chapter, we will review the available literature on human and animal models concerning ?extreme? conditions for spermatogenesis, such as: heat stress, hypoxia and pathological conditions like varicocele, cryptorchidism and diabetes. Our analyses suggest that germ cell apoptosis, oxidative stress and DNA damage are common features in all of these ?extreme? conditions. Furthermore, oxidative damage seems to be present in all of these conditions during the initiation step of cellular damage. This oxidative stress in the testicle is critical when it poses an imminent risk to the viability and quality of the reproductive cells of animals and humans subjected to extreme conditions. Thus, about 25% of infertile patients are diagnosed with elevated levels of reactive oxygen species (ROS) in semen samples. It is well documented that oxidative damage and elevated ROS levels in germ cells lead to apoptosis, a likely cause of hypospermatogenesis and low sperm production in these patients. © 2012 by Nova Science Publishers, Inc. All rights reserved.