Our molecular understanding of the how tumor suppressor gene (TSG) abnormalities contribute to myeloid malignancies is relatively limited. While the NF1 and TP53 TSGs follow the Knudson two-hit paradigm and undergo biallelic inactivation, there is increasing evidence that inactivation of a single allele of TSG such as RUNX1, PU.1 and RPS14 (haploinsufficiency) can also contribute to leukemogenesis. New technologies including high density single nucleotide polymorphism (SNP) arrays, RNA interference (RNAi) and chromosome engineering to develop mouse models with defined genetic rearrangements are emerging as potent tools for cloning and studying the function of TSGs. Notwithstanding these advances, the role of many chromosomal deletions that are commonly observed in myeloid malignancies remains uncertain, particularly the deletion of chromosomes 5, 7, 9 and 20. Since these deletions are often associated with resistance to current therapies, discovering the relevant TSGs and determining how they function in cell growth are high priorities.