The vast quantity of information in our genomes must continuously be read out and processed. This is done by proteins, acting either individually or as part of larger protein complexes. How this genome processing operates successfully, given the crowded nature of the DNA track as well as its mechanical constraints and coiling, is a question of fundamental interest.We will investigate the dynamics of genome processing during DNA transcription and replication. Throughout, we ask the question, what brings these processes to a halt? Focusing on both individual molecular motors and protein complexes, we ask, when do these stall? Both mechanical constraints such as the accumulation of torsional stress and the presence of proteins along the DNA helix may conspire, intentionally or not, to halt transcription and replication.Specifically, we will investigate how RNA polymerases, replicative helicases, and replisomes can be derailed or stalled. These experiments will shed light on the mechanochemical cycle of RNA polymerase, on its motion along a complex track, on the physical interactions that occur between helicases and proteins at termination, and on replisome dynamics near stall. They will also quantify the effects of torsional stress in DNA on the advancement of transcription and replication.The proteins and protein complexes studied here include principal actors in processes essential to cell survival. Understanding the manners in which they can fail will illuminate their mechanism and cellular roles. The powerful single-molecule instrumentation that we have developed in recent years allows one to visualize individual proteins while precisely controlling and monitoring the state of DNA. When harnessed to answer these profound biological questions, we extend not only our knowledge of biological processes but also our understanding of how simple physical principles can govern a wide range of phenomena, thereby having an impact on biology and physics alike.