Somatic hypermutation (SHM) of immunoglobulin (Ig) genes is a highly specific mechanism restricted to B lymphocytes during only a few cell generations. Data presented here suggest that transcription of the target genes is required, but not sufficient for SHM. Presumably,cis–acting elements, such as those present in the Ig enhancers, are required to target a mutator factor (MuF) to Ig and humanBCL–6genes. It is postulated that the MuF travels with the transcribing RNA polymerase and is deposited on the target gene when the polymerase pauses. Point mutations, and rare deletions and insertions, are created by the combined actions of MuF and certain DNA polymerases. A subset of the mutations is corrected during SHM by DNA mismatch repair.