Gram-positive bacteria are leading causes of many types of human infection, including pneumonia, skin and nasopharyngeal infections, as well as urinary tract and surgical wound infections among hospitalized patients. These infections have become particularly problematic because many of the species causing them have become highly resistant to antibiotics. The role of mobile genetic elements, such as plasmids, in the dissemination of antibiotic resistance among Gram-positive bacteria has been well studied; less well understood is the role of mobile elements in the evolution and spread of virulence traits among these pathogens. While these organisms are leading agents of infection, they are also prominent members of the human commensal ecology. It appears that these bacteria are able to take advantage of the intimate association between host and commensal, via virulence traits that exacerbate infection and cause disease. However, evolution into an obligate pathogen has not occurred, presumably because it would lead to rejection of pathogenic organisms from the host ecology. Instead, in organisms that exist as both commensal and pathogen, selection has favored the development of mechanisms for variability. As a result, many virulence traits are localized on mobile genetic elements, such as virulence plasmids and pathogenicity islands. Virulence traits may occur within a minority of isolates of a given species, but these minority populations have nonetheless emerged as a leading problem in infectious disease. This chapter reviews virulence plasmids in nonsporulating Gram-positive bacteria, and examines their contribution to disease pathogenesis. VIRULENCE PLASMIDS IN STAPHYLOCOCCUS AUREUS S. aureus-virulence and pathogenesis Infection with S. aureus can result in a wide variety of diseases, including wound infections, toxic shock, food poisoning, endocarditis, pneumonia, and septicemia (1). Virulence and drug resistance often occur together, as recent outbreak strains of methicillin-resistant S. aureus (MRSA) also produce a number of different virulence factors (2). It is perhaps not surprising that a bacterium capable of causing such a wide array of diseases possesses a diverse repertoire of virulence factors. A consequence of this versatility is that the pathogenesis of S. aureus is usually multifactorial (3). S. aureus is capable of producing a number of extracellular toxins, including cytolytic toxins (α-toxin, β-toxin, γ-toxin), enterotoxins, toxic shock syndrome toxin (TSST-1), and exfoliative toxins. Although staphylococcal virulence is seldom attributable to one factor alone, different toxins have been linked to different types of staphylococcal infection. For example, staphylococcal enterotoxins are associated with food poisoning (4, 5