Most solid tumors show resistance to current chemotherapy. This drug resistance can be associated with the unique physiology of solid tumors. Solid tumors generally have regions of low oxygen (hypoxia), low pH and low levels of glucose, which are not observed in normal tissues. These tumor-specific conditions commonly cause the glucose-regulated stress response of cancer cells. Accumulating evidence shows that the stress response leads to induction of resistance to multiple drugs, such as etoposide, doxorubicin, camptothecin and vincristine. This type of drug resistance is reversible and decays rapidly when stress conditions are removed. The induction of drug resistance can be partly explained by cell cycle arrest at the G1 phase in stressed cells because most anticancer drugs are primarily effective against rapidly dividing cells. Specific mechanisms, such as the decreased expression of DNA topoisomerase (topo) II alpha for the resistance to topo II poisons, are also involved in the drug resistance. Stressed cells, however, become hypersensitive to cisplatin, one of the most effective drugs against solid tumors, suggesting that preferential cytotoxicity to stressed cells may be important for the clinical efficacy against solid tumors. Further characterization of stressed cells will provide a unique target to circumvent the drug resistance of solid tumors.