Since European settlement more than 10 % of Australia's native fauna have become extinct and the current picture reflects 46 % are at various vulnerability stages. Australia's iconic marsupial species, koala (Phascolarctos cinereus) is listed as vulnerable under national environmental law. Human population growth, road expansion and extensive land clearance have fragmented their eucalyptus habitat and reduced the ability of koalas to move across the tree canopy; making the species most vulnerable on the ground. Disease-principally chlamydia, road death, dog-attack and loss of habitat are key environmental pressures and the reasons why koalas are admitted for veterinary care. It is important to understand the dynamics of the physiological impacts that the koala faces from anthropogenic induced environmental challenges, especially on its essential biological functions (e.g. reproduction and immune system function). This review explores published literature and clinical data to identify key environmental stressors that are operating in mainland koala habitats, and while the focus is mostly on the koala, much of the information is analogous to other wildlife; the review may provide the impetus for future investigations involving other vulnerable native wildlife species (e.g. frogs). Oxalate nephrosis associated renal failure appears to be the most prevalent disease in koala populations from South Australia. Other key environmental stressors included heat stress, car impacts and dog attacks. It is possible that maternal stress, nutritional deprivation, dehydration and possible accumulation of oxalate in eucalyptus leaf increase mostly during drought periods impacting on fetal development. We hypothesize that chronic stress, particularly in urban and fringe zones, is creating very large barriers for conservation and recovery programs. Chronic stress in koalas is a result of the synergistic interplay between proximate environmental stressor/s (e.g. heat stress and fringe effects) acting on the already compromised kidney function, immune- and reproductive suppression. Furthermore, the effects of environmental pollutants in the aggravation of diseases such as kidney failure, reproductive suppression and suppression of the unique marsupial immune system should be researched. Environmental policies should be strengthened to increase human awareness of the threats facing the koala, increased funding support towards scientific research and the protection and creation of reserve habitats in urban areas and fringe zones. Global climate change, nutritional deprivation (loss of food sources), inappropriate fire management, invasive species and the loss of genetic diversity represent the complexities of environmental challenges impacting the koala biology.