Analysis of interspecies matings between S. typhimurium and E. coli indicates that the genetic barrier that separates these (and perhaps many other) related species is primarily recombinational. The structural component of this barrier is genomic sequence divergence. The mismatch repair enzymes act as potent inhibitors of interspecies recombination, whereas the SOS system acts as an inducible positive regulator. Interspecies mating triggers a RecBC-dependent SOS response in female bacteria that increases recombination mainly through overproduction of the RecA protein. Mismatch repair acts to reduce the mutation rate and recombination between similar sequences, whereas SOS acts to increase both. These opposing activities allow mismatch repair and SOS systems to determine both the rate of accumulation of sequence divergence and the extent of genetic isolation, which are the key components of the speciation process.