Updated project metadata. Nuclear proteins bind chromatin to execute and regulate genome-templated processes. While structural and biochemical studies of individual nucleosome interactions have suggested that an acidic patch on the nucleosome disk surface may be a common site for recruitment to chromatin, the pervasiveness of acidic patch binding and whether other nucleosome surface binding hot-spots exist remains unclear. Here, we use nucleosome affinity proteomics with a library of nucleosomes that collectively disrupts all exposed histone surfaces to establish the universal principles of nucleosome binding. We find that the acidic patch and two adjacent surfaces are the primary hot-spots for nucleosome disk binding and are critical for the majority of nucleosome-protein interactions. In contrast, nearly half of the nucleosome disk surface participates only minimally in protein binding. In addition to establishing the fundamental principles of chromatin binding, our screen defines nucleosome surface requirements of nearly 300 nucleosome interacting proteins implicated in diverse nuclear processes including transcription, DNA damage repair, cell cycle regulation, and nuclear architecture. Building from our screen, we demonstrate that the Anaphase-Promoting Complex/Cyclosome directly binds the acidic patch and elucidate a redundant charge-based mechanism of acidic patch binding by nuclear pore protein ELYS. Overall, our interactome screen illuminates a highly competitive nucleosome binding hub for chromatin-targeted activities and curates a list of nucleosome interacting proteins that will enable mechanistic exploration of many unexpected chromatin-templated nuclear processes.