Because of its importance as a major human and animal pathogen, Staphylococcus aureus has been the focus of intensive research efforts. At the time of writing, the genomes of 14 isolates of S. aureus have been published and released into the public domain with many more genome sequencing projects underway, representing an excellent resource for studies of bacterial evolution and pathogenesis. Recently, whole genome sequences of several other species of the Staphylococcus genus have been completed allowing a comparative genomic analysis of the adaptation of different species to their natural habitats. Here, we summarize selected comparative genomic studies that have contributed to our understanding of how staphylococci adapt to different environments, combat antibiotics and acquire increased virulence.