Post-translational methylations play central roles in epigenetic gene regulation pathways that are central to stem cell regulation. Lysine methylations are turn-on switches for hundreds of distinct protein-protein interactions among a diverse family of cell regulators called epigenetic reader proteins. In spite of their biological importance and relevance to therapeutic development, there exist few synthetic agents that can help us to study or antagonize these pathways. We have been developing chemicals that can mimic, sense, or antagonize the lysine-methylation-driven biochemistry important to healthy and disease-linked cellular processes. We have created organic macrocycles that can recognize and bind to methylated sites on proteins, including examples that disrupt methylation-driven protein-protein interactions and others that can provide a readout of a proteins methylation state. We have also targeted a family of methylation reader proteins called chromodomains, having created antagonists of the epigenetic master controller Chromobox homolog 7 (CBX7) that is a master controller of stem cell programming. We will report on the impacts of these new inhibitors on the programming of cancer cells and stem-like cancer cells, and discuss implications for developing new treatments for stem-like cancers that tend to have the most aggressive and untreatable clinical manifestations.