TP53 encodes p53, a tumor suppressor protein that consists of transactivation domain, proline-rich domain, DNA-binding domain, oligomerization domain, and regulatory domain. p53 responds to diverse cellular stresses to maintain genomic stability and to induce cell cycle arrest, apoptosis, DNA repair and metabolic changes. TP53 mutations represent an important mechanism of resistance to DNA-damaging chemotherapeutic agents. Somatic TP53 mutations are found in a variety of cancers with various frequencies depending on cancer type; overall, TP53 is mutated in over one-half of human cancers. Missense mutations were the most frequent (~70-80%), followed by frameshift and nonsense mutations. Most TP53 mutations are clustered in the DNA-binding domain encompassing exons 5 and 8. These mutations either directly disrupt the DNA-binding domain of TP53 or cause conformational changes of the TP53 protein, thus leading to severely impaired TP53 function. Overall in myeloid malignancies, TP53 mutations are found in 5% to 15% of de novo MDS and AML but 20% of myelodysplastic syndrome with isolated del(5q) and ~50% of MDS/AML with complex karyotype. TP53 mutations are also more frequent in therapy-associated myeloid neoplasm (21-38%) compared to de novo MDS and AML. TP53 mutations are also found in 8% of blastic plasmacytoid dendritic cell neoplasm, and less than 5% in myeloproliferative neoplasms (ET, PV and PMF) and chronic myelomonocytic leukemia. TP53 mutations are independently associated with a poor prognosis in myelodysplastic syndrome (NCCN Guidelines for Myelodysplastic Syndromes) and is a poor risk factor in AML (NCCN Guildelines for AML). TP53 mutations are also associated with resistance to lenalidomide or relapse during lenalidomide treatment. TP53 mutations are independently associated with unfavorable outcomes and shorter survival after hematopoietic stem cell transplantation in patients with myelodysplastic syndrome and myelodysplastic syndrome/acute myeloid leukemia, but an increased response to decitabine in patients with myelodysplastic syndrome or acute myeloid leukemia.