Many anti-cancer drugs used in the clinic today damage DNA, resulting in cell death either directly or following DNA replication. Many anti-cancer drugs are exclusively toxic to replicating cells and toxic lesions are formed when a replication fork encounters a damaged DNA template. Recent work shows that replication lesions, similar to those produced during anti-cancer therapy, are commonly associated with cancer aetiology. DNA replication lesions are present in cancer cells owing to oncogene expression, hypoxia or defects in the DNA damage response or DNA repair. Here, I review how novel therapies can exploit endogenous replication lesions in cancer cells and convert them to toxic lesions. The aim of these therapies is to produce similar lesions to those produced by DNA damaging anti-cancer drugs. The difference is that the lesions will be cancer-specific and produce milder side-effects in non-cancerous cells.