Staphylococcus aureus is the single most important bacterial pathogen in infections among drug users. It is responsible for several diseases, ranging from superficial cutaneous abscesses to life-threatening intravascular infections. Although the nature of these infections is well described in published work, there is limited understanding of their epidemiology and pathogenesis. This limitation is in part due to the difficulty of studying disease transmission among drug users in the community, and the limitations of the investigative tools that have so far been used. We review the current understanding of the pathogenesis of staphylococcal disease in drug users and argue for the integration of molecular epidemiological techniques and social network methodology to increase our understanding of the basis for the persistence, distribution, and transmission dynamics of S aureus among drug users. Finally, we propose a framework for investigating the transmission of pathogens in community-based settings.