In the review, we discuss the features of monoallelic and biallelic TP53 mutations within MDS, the carcinogenic mechanisms, and the predictive value of TP53 variants in current standard treatments including hypomethylating agents, allogeneic hematopoietic stem cell transplantation, and lenalidomide, as well as the latest progress in TP53-targeted therapy strategies in MDS. The gene discussed is TP53; the disease is myelodysplastic syndrome.