Chemotherapy is often the only treatment for relapse of brain tumors and should increase the survival of patients with gliomas. Although new anticancer drugs have been discovered, the number of active drugs in these tumors is very low. Several biological mechanisms decrease the efficacy of chemotherapy: cellular kinetics, heterogeneity and micro-environment of brain tumors, and the classical blood-brain barrier. Moreover, several mechanisms of chemoresistance, identified in other tumors, should be involved in intrinsic chemoresistance. These biological factors, which are involved simultaneously or successively suggest that the chemotherapy currently used in brain tumors cannot increase the response rate; even if high dose chemotherapy with autologous bone marrow transplantation or intratumor administration of drugs are used.