Therapy-related myelodysplasia and acute myeloid leukemia (t-MDS/AML) are malignancies occurring after exposure to chemotherapy and/or radiotherapy. Several studies have addressed cumulative dose, dose intensity and exposure to specific agents of preceding cytotoxic therapy in relation to the risk of developing such leukemia. Since only a small percentage of patients exposed to cytotoxic therapy develop t-MDS/AML, it has been suggested that some genetic predisposition may be involved, specifically associated to polymorphisms in certain genes involved in chemotherapy/radiotherapy response - fundamentally genes intervening in drug detoxification and DNA synthesis and repair. A review is made of the genetic studies related to t-MDS/AML predisposition, focusing on the mechanistic findings of how specific chemotherapeutic drug exposure produces DNA damage and induces the chromosomal abnormalities characteristic of t-MDS/AML, the molecular pathways involved in repairing such drug induced damage, and the way in which they influence t-MDS/AML genesis. Specific issues are (a) the interaction of topoisomerase II inhibitors, alkylators and antimetabolite drugs with DNA repair mechanisms and their impact on t-MDS/AML leukemogenicity and (b) the influence of DNA polymorphisms in genes involved in DNA repair, drug metabolization and nucleotide synthesis, paying special attention to the relevance of folate metabolism. Finally, we discuss some aspects relating to study design that are most suitable for characterizing associations between drug exposure and genotypes related to t-MDS/AML risk - stressing the importance of the inclusion of chemotherapy-exposed control groups.