The incidence of therapy-related myelodysplastic syndromes (t-MDS) is increasing as the number of cancer survivors is increasing. While t-MDS is currently defined descriptively by prior receipt of chemotherapy and/or radiotherapy, some forms of MDS that occur post localized radiation monotherapy, biologically and clinically resemble de novo (d)-MDS more than t-MDS, and therefore may not be truly therapy-related. Although patients with t-MDS, as a group, fare worse than patients with d-MDS, a variation in individual outcomes of patients with t-MDS has increasingly been appreciated. As such, accurate risk stratification is important for counseling of patients and for clinical decision making. Most of the current clinical tools used for prognostication in t-MDS were developed for d-MDS and were not specifically validated in patients with t-MDS. The management of patients with t-MDS remains challenging, highlighting the importance of developing effective prevention strategies as well as newer, targeted, and rationally-designed therapeutic interventions.