Nucleosomes are fundamental repeating units of chromatin, which facilitate genomic DNA packaging and serve as signal integration hubs for genome templated processes. Through a series of comprehensive proteomic screens we demonstrated that a group of acidic amino acids referred to as the acidic patch on the nucleosome disk surface is a hot spot for chromatin binding. We revealed severely disrupted chromatin binding in nucleosomes containing acidic patch mutations found in numerous cancers. Finally, we identified nucleosome binding patterns for hundreds of proteins representing diverse nuclear functions, many of which were novel chromatin binders. To follow up our screen results, we investigated mechanisms of nucleosome and DNA-free histone binding by established and novel chromatin enzymes using cryo-EM. I will discuss the nucleosome interactome screens and two structural projects that the screens inspired, the first focused on a class of JmjC-containing domain KDM2A/B histone demethylases and the second on the Anaphase Promoting Complex/Cycleosome.