Abstract Epigenetic modifications are dynamic and reversible processes that regulate gene expression without altering the underlying sequence of the DNA. Gene expression is instead controlled by chromatin modifications, such a DNA methylation, histone modification, and chromatin remodeling. Proteins involved in epigenetic modifications are categorized as writers, which modify the chromatin; readers, that recognize the modifications; and erasers which remove the modifications. While essential for cellular function, abnormal expression or alteration of the proteins involved in epigenetic regulation leads to diseases, such as cancer. Due to their role in disease, epigenetic modifiers are attractive targets for the discovery and development of novel therapeutics. Research in the field has shown many epigenetic proteins are druggable and several FDA-approved drugs have already been developed (Ref. 1). At Reaction Biology we offer a suite of services for epigenetic drug discovery, including the largest panel for epigenetic screening and profiling in the industry with over 30 Methyltransferases, 100+ Reader Domain Proteins, HATs, HDACs, Demethylases, DUBs, PARPs, and more. In order to directly probe the strength of the binding interaction between the epigenetic target and potential therapeutics we offer biophysical assays, such as surface plasmon resonance (SPR), isothermal titration calorimetry (ITC), and microscale thermophoresis (MST). Here we present SPR binding data for three epigenetic targets: NSD2 (writer), PRMT5 (writer), and Bromodomain-4 (reader). Through the use of commercially available controls, we developed SPR assays for these targets that can be used to screen compound or fragment libraries, determine kinetics/affinity, and profile binding specificity. (Ref 1.) V. Prachayasittikul et al (2017) Exploring the epigenetic drug discovery landscape. Expert Opin. Drug Discov. 12(4): 345-362. Citation Format: Rebecca Eells, Lynn K. Baker, Christopher Bray, Haiching Ma. Measuring direct binding to epigenetic targets using SPR [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4014.