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The bacterial pathogen Legionella pneumophila is found ubiquitously in fresh water environments where it replicates within protozoan hosts. When inhaled by humans it can replicate within alveolar macrophages and cause a severe pneumonia, Legionnaires disease. Yet much needs to be learned regarding the mechanisms that allow Legionella to modulate host functions to its advantage and the regulatory network governing its intracellular life cycle. The establishment and publication of the complete genome sequences of three clinical L. pneumophila isolates paved the way for major breakthroughs in understanding the biology of L. pneumophila. Based on sequence analysis many new putative virulence factors have been identified foremost among them eukaryotic-like proteins that may be implicated in many different steps of the Legionella life cycle. This review summarizes what is currently known about regulation of the Legionella life cycle and gives insight in the Legionella-specific features as deduced from genome analysis.