ABSTRACT Whole-genome sequences are now available for all the clinically important clostridia and many of the lesser or opportunistically pathogenic clostridia. The complex clade structures of C. difficile , C. perfringens , and the species that produce botulinum toxins have been delineated by whole-genome sequence analysis. The true clostridia of cluster I show relatively low levels of gross genomic rearrangements within species, in contrast to the species of cluster XI, notably C. difficile , which have been found to have very plastic genomes with significant levels of chromosomal rearrangement. Throughout the clostridial phylotypes, a large proportion of the strain diversity is driven by the acquisition and loss of mobile elements, including phages, plasmids, insertion sequences, and transposons. Genomic analysis has been used to investigate the diversity and spread of C. difficile within hospital settings, the zoonotic transfer of isolates, and the emergence, origins, and geographic spread of epidemic ribotypes. In C. perfringens the clades defined by chromosomal sequence analysis show no indications of clustering based on host species or geographical location. Whole-genome sequence analysis helps to define the different survival and pathogenesis strategies that the clostridia use. Some, such as C. botulinum , produce toxins which rapidly act to kill the host, whereas others, such as C. perfringens and C. difficile , produce less lethal toxins which can damage tissue but do not rapidly kill the host. The genomes provide a resource that can be mined to identify potential vaccine antigens and targets for other forms of therapeutic intervention.