Chromatin associated complexes are frequently mutated in human cancers and these mutations are particularly prevalent in leukemia. The prevailing hypothesis is that mutations in chromatin regulatory complexes lead to aberrant transcriptional control of critical gene expression programs that support the survival, proliferation, and self-renewal of cancer cells. There has been significant effort focused on the discovery and development of small molecules that target chromatin-associated (epigenetic) complexes. Multiple generations of small molecules have led to some success in therapeutic development but, until recently, no therapeutic has been sufficiently active to drive the development of acquired genetic or adaptive resistance as is often seen with small molecules that target tyrosine kinases. We have focused on the development of small molecules that target chromatin associated complexes important for aberrant control of developmental and stem cell associated gene expression in leukemia and sarcomas including the DOT1L, KMT2A, KAT6A, LSD1 and other complexes. A recent interest has been the discovery and development of potent, selective, and orally bioavailable small molecules that inhibit the protein-protein interaction between the histone methyltransferase KMT2A (MLL1) and the critical scaffolding protein MENIN encoded by the Multiple Endocrine Neoplasia 1 (MEN1) gene. The impressive preclinical activity of this approach has driven the rapid clinical development of small molecules that are now in phase I/II clinical trials and the recent approval of Revumenib for the treatment of patients with KMT2A-rearranged AML. We described the development of mutational acquired resistance to revumenib, a small molecule KMT2A -MENIN inhibitor, in the initial phase I trial. These acquired mutations arise in the small molecule biding site and lead to structural changes that decrease the potency of binding. Thus, the inhibitor no longer removes the MENIN-KMT2A complex from chromatin and no longer reverses leukemogenic gene expression. These findings fully validate MENIN, and chromatin complexes more broadly, as relevant therapeutic targets in human cancers. Subsequent work has identified novel mechanisms of resistance that are driven by mutations other than those described above and adaptive, non-mutational forms for resistance. This has led to the search for and identification of rational combinations that should be more effective and may prevent the development of resistance. Furthermore, these combinations appear to be effective in other types of cancer as well. Current studies focused on MENIN inhibitor resistance mechanisms beyond MENIN mutations and other therapeutically tractable chromatin complexes will be discussed.