Histone modification is one of the processes that defines the epigenetic landscape and is involved in the regulation of genome-wide gene expression. Some of these modifications are transient and can fluctuate during the cell cycle. In their ‘Tools and Resources’ article, Yoko Hayashi-Takanaka, Hiroshi Kimura and colleagues (Hayashi-Takanaka et al., 2020) describe a powerful tool to monitor the fluctuations of these changes. This approach is based on widefield fluorescence microscopy of single cells stained either with labelled antibodies against multiple histone modifications or fluorescent dyes. The relative abundance of the labelled histone modifications is then quantified for hundreds of cells. To validate the method, the authors monitored changes in histone modification during cell cycle progression and in response to overexpression of lysine demethylases, which target specific lysine residues on histone proteins, and obtained similar results to those previously reported. Moreover, to assess the capability of the method to identify relevant inhibitors of specific histone modifications, they performed a chemical screen of extracts of marine organisms, which resulted in the isolation of a known histone deacetylase inhibitor, psammaplin A. Taken together, this analytical system represents a robust and easy-to-use tool that will not only be useful to study histone modifications, but also the dynamics of other nuclear proteins and their modifications.