Our dream of determining the entire Escherichia coli K12 genome sequence has been realized. This calls for new approaches for the analysis of gene expression and function in biology's best-understood organism. Comparison of the E. coli genome sequence with others will provide important taxonomic insights and have implications for the study of bacterial virulence. Approximately 20% of E. coli genes have been designated FUN genes, because they have no known function or homologies to sequence databases. FUN genes promise to have an exciting impact on bacterial research. The post-genome era requires novel strategies that address gene regulation at the level of the entire cell. These strategies need to supersede the reductionist approach to genetic analysis. Only then will the genome sequence lead us to an understanding of how a bacterial cell really works.