Staphylococci, and in particular Staphylococcus aureus, cause an extensive variety of infections in a range of hosts. The comprehensive analysis of staphylococcal genomes reveals mechanisms controlling the organism's biology, pathobiology, and dissemination. Whole-genome sequencing technologies led to a quantum leap in our understanding of bacterial genomes. The recent cost reduction of sequencing has resulted in unprecedented volumes of genomic information about S. aureus, one of the most sequenced bacterial species. Collecting, comparing, and interpreting big data is challenging, but fascinating insights have emerged. For example, it is becoming clearer which selective pressures staphylococci face in their habitats and which mechanisms allow this pathogen to adapt, survive, and spread. A key theme is the constant evolution of staphylococci as they alter their genome, exchange DNA, and adapt to new environments, leading to the emergence of increasingly successful, antibiotic-resistant, immune-evading, and host-adapted colonizers and pathogens. This article introduces the structure of staphylococcal genomes, details how genomes vary between strains, outlines the mechanisms of genetic variation, and describes the features of successful clones.