By a multiplicity of mechanisms, hypoxia and acidosis create a nurturing environment for tumor progression and the evolution of metastatic, drug-resistant cells. Acidosis drives mutagenesis and promotes the subversion of checkpoints and apoptotic mechanisms. Hypoxic tissues secrete cytokines that undermine normal anti-tumor surveillance by macrophages, turning them into accomplices and facilitators of invasion and angiogenesis. Invasiveness is also abetted by acidosis, the result of shifting to an anaerobic glycolytic metabolism. These factors explain the generally poor prognosis indicated by tumors expressing hypoxia-inducible factor-1 (HIF-1). However, these insights into the physiology of hypoxic tumors have inspired the development of new chemotherapeutic approaches directed at these tissues, including bioreductive drugs and gene therapies, some of which are in clinical trials. The ability to target the hypoxic compartment should allow longer progression-free survival and overall survival of patients bearing solid tumor malignancies.