The human leukaemia develops with abnormal increase of blast cells in the bone marrow. Leukaemia is caused by genetic aberrations which activates proto-oncogenes and inactivates tumor-suppressor genes and eventually leads to leukemogenesis. Myelodysplastic syndrome is a preleukemic state which shares similar symptoms and causative factors as leukaemia. FOXO3 and c-Myc have been increasingly recognized as key regulatory genes involved in the initiation and development of leukaemia and myelodysplastic syndromes. Their roles in these diseases is being investigated and findings thus far has indicated that FOXO3 acts as a tumor suppressor while c-Myc has been identified as a proto-oncogene. Currently published literature indicate that there are limited research on the correlation between FOXO3 and c-Myc especially in leukaemia and myelodysplastic syndrome. This review will focus on the key regulatory roles of FOXO3 and c-Myc in leukaemia and myelodysplastic syndrome.