DNA double-strand breaks (DSBs) are a severe threat to genome stability, as DSB-repair mechanisms with low fidelity contribute to loss of genome integrity. Break-induced replication (BIR) is a crucial DSB-repair pathway when classical homologous recombination mechanisms fail. BIR is often triggered by stalled or collapsed replication forks, following extensive end resection that generates a single-stranded DNA substrate, which can engage either canonical homology-driven BIR, or microhomology-mediated BIR (mmBIR), which requires shorter sequence homologies than does canonical BIR. BIR is a double-edged sword: it is necessary for DSB repair, but is also culpable for introducing mutations and structural variations that are linked to cancer and genetic disorders. In this Review, we discuss BIR regulation in mammalian cells, and the role of BIR in telomere maintenance and in human disease, as well as in genome engineering. We highlight emerging findings in these areas and advances in technologies that have enabled their discovery and reshape our understanding of this enigmatic repair mechanism.