The ability to track individual biomolecules in live cells allows scientists to better understand the interactions between, for example, two proteins or a protein and DNA. Although methods exist to image single biomolecules in bacterial cells, imaging them in larger mammalian cells is challenging. Harvard University’s X. Sunney Xie and colleagues have now developed a fluorescence microscopy technique, called reflected light sheet microscopy, that illuminates proteins in the nucleus of living mammalian cells (Nat. Methods, DOI: 10.1038/nmeth.2411). The technique involves reflecting a thin sheet of light off a mirror—a disposable atomic force microscope cantilever coated with aluminum—so that the sheet slices horizontally through the cell and its nucleus. With the method, the team can detect fluorescently tagged proteins with nanometer spatial and millisecond time accuracy. In addition, the imaging can conveniently be carried out in the same commercially available glass-bottom culture dishes that are used to grow the cells. Xie and coworkers demonstrated the technique by imaging different transcription factors and their interactions with DNA and each other.