Even for the simplest organisms that can be grown in laboratory media, such as bacteria of the mycoplasma family, we are far from understanding all of the design principles and essential functions needed to sustain life. For instance, more than a quarter of the 370 essential protein-coding genes of Mycoplasma genitalium have no known function1. Three recent papers in Science2,3,4, by a consortium of research groups led by Peer Bork, Luis Serrano and Anne-Claude Gavin, illustrate the complexity of Mycoplasma pneumoniae through comprehensive analyses of its transcriptome2, proteome3 and metabolome4. M. pneumoniae has one of the smallest known genomes of a self-replicating bacterium, comprising 816 kb and encoding just 689 proteins, only 8 of which are predicted to be transcription factors. The observation that 89 of the 117 new transcripts identified are antisense to annotated genes reveals a hitherto unappreciated level of gene regulation2. Moreover, many genes were found to produce more than one transcript2. Proteome analysis showed that at least 90% of the proteins studied are part of at least one of the 178 protein complexes identified3. More than half of these complexes had not been described previously. Reconstruction of the metabolic network revealed that many redundancies and branched pathways common to other organisms are not present in M. pneumoniae4. However, despite its low number of metabolic enzymes and transcriptional regulators, the bacterium is able to perform a large variety of metabolic reactions and to adapt quickly to changes in the environment. The former can be explained by the large fraction of multifunctional enzymes, whereas the latter suggests a level of regulation different from that of bacteria with larger genomes. Taken together, the papers highlight the complexity of even the simplest bacteria and underscore the challenges in understanding and reconstructing minimal life forms. More information can be found in commentaries by Venter and colleagues1 and Ochman and Raghavan5.