The article introduces CUT&Tag, an enzyme-tethering strategy for high-resolution chromatin profiling in small samples and single cells. CUT&Tag uses a protein A-Tn5 transposase fusion protein to generate fragment libraries with low background noise, enabling efficient and cost-effective epigenomic profiling. The method is demonstrated to profile histone modifications, RNA Polymerase II, and transcription factors in low cell numbers and single cells. CUT&Tag is compared with other methods like ChIP-seq and CUT&RUN, showing superior signal-to-noise ratios and lower background levels. The technique is also validated for profiling transcription factor binding and chromatin accessibility, and it is shown to be effective in single-cell chromatin profiling, providing discriminatory power for cell type identification. The authors conclude that CUT&Tag is a powerful tool for chromatin profiling, offering high resolution and sensitivity, and is suitable for high-throughput pipelines and clinical applications.The article introduces CUT&Tag, an enzyme-tethering strategy for high-resolution chromatin profiling in small samples and single cells. CUT&Tag uses a protein A-Tn5 transposase fusion protein to generate fragment libraries with low background noise, enabling efficient and cost-effective epigenomic profiling. The method is demonstrated to profile histone modifications, RNA Polymerase II, and transcription factors in low cell numbers and single cells. CUT&Tag is compared with other methods like ChIP-seq and CUT&RUN, showing superior signal-to-noise ratios and lower background levels. The technique is also validated for profiling transcription factor binding and chromatin accessibility, and it is shown to be effective in single-cell chromatin profiling, providing discriminatory power for cell type identification. The authors conclude that CUT&Tag is a powerful tool for chromatin profiling, offering high resolution and sensitivity, and is suitable for high-throughput pipelines and clinical applications.