Post-translational modifications (PTMs) of histones, proteins onto which DNA is packaged, are involved in many biological processes, including transcription, recombination, and chromosome segregation. As these PTMs can be dynamic, combinatorial, and mediators of weak interactions, the comprehensive profiling of all proteins that recognize histone PTMs is a daunting task. Here we describe all approach to design probes that call be used to identify proteins that directly interact with modified histories. Protein structure was used to guide the introduction of a photo-cross-linker in the probe, so as to convert weak interactions into covalent linkages. The probe also included an alkyne group to facilitate click chemistry-mediated Conjugation of reporter tags for the rapid and sensitive detection (via rhodamine) and affinity enrichment (via biotin) of labeled proteins. In particular, we developed and validated a probe that call selectively capture proteins that recognize trimethyled lysine-4 of histone H3 (H3K4me3) in whole proteomes. A complete profiling of H3K4Me3 binding proteins should shed new light on cellular processes regulated by this PTM.