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The relationships between Mycoplasma agassizii, a causative agent of upper respiratory disease (URTD), and desert tortoise (Gopherus agassizii), generally illustrate the complexities of disease dynamics in wild vertebrate populations. In this review, we summarize current understanding of URTD in Mojave desert tortoise populations, we illustrate how inadequate knowledge of tortoise immune systems may obfuscate assessment of disease, and we suggest approaches to future management of URTD in desert tortoise populations. We challenge the view that M. agassizii causes consistent levels of morbidity and/or mortality across the Mojave desert. Instead, URTD may be described more accurately as a context-dependent disease. In addition, new evidence for relatively high levels of natural antibodies to M. agassizii in desert tortoises suggests possible problems in conventional diagnostic tests of disease in tortoises as well as a possible tortoise immune mechanism to protect against M. agassizii. Partly because of the problems in diagnostic testing, we recommend abandoning policies to euthanize tortoises that test positive for an immune response to M. agassizii. Based on this review, we question management strategies aimed solely at reducing Mycoplasma spp. in desert tortoise populations, and advocate a more careful consideration of extrinsic factors as a cause of symptomatic disease. (C) 2009 Elsevier Ltd. All rights reserved.