This dissertation broadly focuses on the discovery of novel small molecule receptors for trimethyllysine (Kme3) and the detailed characterization of the mechanisms through which they achieve their selectivity. In the first section, an iterative redesign approach was employed to improve the known receptor A2B, resulting in the novel receptor A2N, which is a nanomolar binder for Kme¬3. A2N binds Kme3 with 10-fold improved affinity and 5-fold improved selectivity over Kme2 compared to A2B. This is a testament to the power of using iterative redesign for improving receptors, and it suggests that further enhancements in affinity and selectivity are possible through additional rounds of redesign. In the context of different histone peptide sequences, we found the binding properties of A2N to be sensitive to the presence of Lys and Arg residues neighboring a site of Kme3 recognition. To gain a better understanding of how these residues alter the binding interaction, we used a poly-Gly model peptide to specifically investigate the strength and distance dependence of the neighboring secondary interactions. We determined that both residues are capable of binding to the outside of the receptor, producing a multivalent interaction that improves the affinity of A2N for both Kme0 and Kme3, while weakening the selectivity for Kme3 over Kme0. Our results emphasize the challenge inherent in designing non-sequence specific receptors, but lend insight into design principles that will aid the future development of such pan-selective receptors In the final section, synthetic methods were developed for the fine-tuned modification of the carboxylic acids on all Waters group receptors. These methods enabled us to synthesize a series of A2B and A2N derivatives whose outer carboxylic acids were systematically distanced from the receptors, allowing us to study their contributions to the primary interaction with Kme3 and the secondary interaction with Arg or Lys. We discovered that spacing the carboxylates has a direct effect on the affinity and selectivity of each receptor for Kme3 within the binding pocket. Further, our results using A2N indicated that increased spacing weakens the secondary interaction with Arg more dramatically than the primary interaction with KmeX, suggesting that with enough spacing, a completely non-sequence specific variant of A2N could be designed. The techniques developed for functionalizing the receptors also allowed us to generate a series of biotinylated derivatives of A2B, A2N, A2D and A2G that were directly applicable to peptide microarrays (in collaboration with Brian Strahl). Our results indicated that the receptors bind to the arrays, albeit in a non-selective fashion based upon the PTMs present on the bound peptides. We are currently working to optimize these biotinylated receptors, as well as the buffer conditions used for the microarray experiments, to increase the sensitivity of Kme3 detection. In the final section, we report the coupling of an environmentally sensitive dye to A2B to enable an intramolecular indicator displacement assay (IDA) for Lys methylation. While optimization of this system is still underway, it is clear that the techniques developed for modifying our receptors will enable the rapid generation of novel receptors for diverse applications related to Kme3 sensing.