Experimental microbiology in the postgenomic era has survived the first wave of uncertainty: a perspective of being replaced by in silico microbiology. Although it is clear now that experimental science is irreplaceable, we are facing yet another wave: the frustration of having a half million microbial genes in databases but lacking simple ways of getting biologically relevant information. Therefore, it is reassuring to see some clear water between the waves: examples of experimental research that takes advantage of a comparative genomic approach one step at a time. The paper by Karniol and Vierstra in this issue (10) describing a new family of histidine kinases shows how the use of simple bioinformatics tools by microbiologists can (i) identify new targets for experimental work and (ii) provide important feedback for improving these tools.