Evolution has shaped all living organisms on Earth, although many details of this process are shrouded in time. However, it is possible to see, with one's own eyes, evolution as it happens by performing experiments in defined laboratory conditions with microbes that have suitably fast generations. The longest-running microbial evolution experiment was started in 1988, at which time twelve populations were founded by the same strain of Escherichia coli. Since then, the populations have been serially propagated and have evolved for tens of thousands of generations in the same environment. The populations show numerous parallel phenotypic changes, and such parallelism is a hallmark of adaptive evolution. Many genetic targets of natural selection have been identified, revealing a high level of genetic parallelism as well. Beneficial mutations affect all levels of gene regulation in the cells including individual genes and operons all the way to global regulatory networks. Of particular interest, two highly interconnected networks—governing DNA superhelicity and the stringent response—have been demonstrated to be deeply involved in the phenotypic and genetic adaptation of these experimental populations. BioEssays 29:846–860, 2007. © 2007 Wiley Periodicals, Inc.