The availability of leptospiral genome sequences has allowed comparative genomics analyses of pathogenic, saprophytic and intermediate species. These studies have identified a set of core leptospiral genes and suggested that intermediate species are more closely related to pathogenic species, but retain the enhanced metabolic capacity of saprophytic species. Genes of unknown function are over-represented in the pathogen-specific gene subsets, suggesting pathogenic mechanisms in leptospirosis are unique to Leptospira. Likewise, whole genome transcriptomics studies have found that genes upregulated under simulated in vivo conditions generally have no defined function. The advent of methods for constructing defined transposon mutants in pathogenic Leptospira has allowed for the first time an investigation of specific virulence factors involved in acute disease. These studies have now identified several essential virulence factors, including LPS, motility, catalase, heme oxygenase, the stress proteins ClpB and HtpG, the uveitis-associated protein LruA, and the OmpA-like protein Loa22. Also of interest has been the finding that many previously predicted virulence genes are not essential for the ability of Leptospira to cause disease, consistent with the notion of a degree of functional redundancy for virulence-associated genes. At least 25 leptospiral proteins, in recombinant form, have been shown to adhere to a range of mammalian cellular components. In many cases, the same protein was found to bind to multiple host components. However, unequivocal genetic evidence for a role in virulence is lacking for almost all of these putative adhesins. A high throughput screen of transposon mutants has allowed the identification of virulence genes of unknown function and has also identified for the first time genes required for renal colonization of the carrier host.