Bianco and his team use a combination of bulk-phase biochemical and single-molecule biophysical approaches to understand the molecular basis of stalled DNA replication fork rescue, an essential process required to maintain genome stability. When forks are not rescued the consequences for the cell can be disastrous leading to cell death or in higher eukaryotes, cancer. Experimental work is concerned with the function and regulation of the complexes that mediate fork rescue, with studies focused primarily on the role of the single-strand DNA binding protein (SSB) and several recombination enzymes, using Escherichia coli as the model organism.