Is the body's natural flora capable of evolving over time to become more virulent? Could evolvable virulence explain why some people suffer invasive bacterial infections while others do not? Despite its notoriety as a dangerous hospital-associated pathogen, Staphylococcus aureus is a commonly carried commensal, found in the noses of 30% of adults. From the perspective of the bacteria, invasive disease occurs rarely compared to asymptomatic carriage. In previous work, we investigated the evolutionary dynamics of nasal carriage, and discovered that in one long-term nasal carriage population an excess of protein-truncating substitutions was associated with the transition to a life-threatening invasive blood stream infection. Here, we report results of population-based and molecular studies we are conducting into the role of genetics and within-host evolution in the progression of invasive Staphylococcus aureus disease.