Genome replication and gene expression are carried out by macromolecular machines that exist at nanometer scale and generate piconewton forces. Challenged by the hierarchical chromatin organization and omnipresent thermal fluctuations, these DNA-based machines still accomplish their tasks with remarkable efficiency and accuracy. We leverage the cutting-edge single-molecule toolkit to follow dynamic, stochastic, and heterogeneous molecular events in real time, and complement these biophysical investigations with advanced biochemical, structural, and genomic assays. This multidisciplinary approach enables us to gain unprecedented insights into the principles of generic and epigenetic inheritance.