Biomarkers are biological molecules found in body fluids or tissues, which can be considered as indications of a normal or abnormal process, or of a condition or disease. There are various types of biomarkers based on their application and molecular alterations. Treatment-sensitivity or drug resistance biomarkers include prognostic and predictive molecules with utmost importance in selecting appropriate treatment protocols and improving survival rates. Acute lymphoblastic leukemia (ALL) is the most prevalent hematological malignancy diagnosed in children with nearly 80% cure rate. Despite the favorable survival rates of childhood ALL (chALL), resistance to chemotherapeutic agents and, as a consequence, a dismal prognosis develops in a significant number of patients. Therefore, there are urgent needs to have robust, sensitive, and disease-specific molecular prognostic and predictive biomarkers, which could allow better risk classification and then better clinical results. In this article, we review the currently known drug resistance biomarkers, including somatic or germ line nucleic acids, epigenetic alterations, protein expressions and metabolic variations. Moreover, biomarkers with potential clinical applications are discussed.