Therapy-related myeloid neoplasm (t-MN) is a distinctive clinical syndrome occurring after exposure to chemotherapy or radiotherapy. t-MN arises in most cases from a multipotential hematopoietic stem cell or, less commonly, in a lineage committed progenitor cell. The prognosis for patients with t-MN is poor, as current forms of therapy are largely ineffective. Cytogenetic analysis, molecular analysis and gene expression profiling analysis of t-MN has revealed that there are distinct subtypes of the disease; however, our understanding of the genetic basis of t-MN is incomplete. Elucidating the genetic pathways and molecular networks that are perturbed in t-MNs, may facilitate the identification of therapeutic targets that can be exploited for the development of urgently-needed targeted therapies.