Until about 15 years ago, the molecular and cellular basis for pathogenesis in leptospirosis was virtually unknown. The determination of the first full genome sequence in 2003 was followed rapidly by other whole genome sequences, whose availability facilitated the development of transposon mutagenesis and then directed mutagenesis of pathogenic Leptospira spp. The combination of genomics, transcriptomics and mutant construction and characterisation has resulted in major progress in our understanding of the taxonomy and biology of Leptospira. The most recent advances are analysed and discussed in this chapter.