The microenvironmental physiology of tumors is uniquely different from that of normal tissues. It is characterized, inter alia, by O(2) depletion (hypoxia, anoxia), glucose and energy deprivation, high lactate levels, and extracellular acidosis, parameters that are anisotropically distributed within the tumor mass. This hostile microenvironment is largely dictated by the abnormal tumor vasculature and heterogeneous microcirculation. Hypoxia and other hostile microenvironmental parameters are known to directly or indirectly confer resistance to irradiation leading to treatment failure. Hypoxia directly leads to a reduced "fixation" of radiation-induced DNA damage. Indirect mechanisms include a restrained proliferation, changes in gene expression and alterations of the proteome (eg, elevated activity of DNA-repair enzymes and resistance-related proteins, increased transcription of growth factors), and genomic changes (genomic instability leading to clonal heterogeneity and selection of resistant clonal variants). These changes, caused by the hostile microenvironment, can favor tumor progression and acquired treatment resistance, both resulting in poor clinical outcome and prognosis. Pretreatment assessment of critical microenvironmental parameters is therefore needed to allow the selection of patients who could benefit from special treatment approaches (eg, hypoxia-targeting therapy). Because of a relatively high risk of local relapse or distant metastasis, patients with hypoxic and/or "high-lactate" tumors should undergo close surveillance.