Staphylococcus aureus is a leading cause of hospital-acquired and often persistent infections. A key feature of pathogenic S. aureus is the expression of an array of extracellular matrix-binding proteins. In particular, the fibronectin-binding proteins FnBP-A and FnBP-B afford the pathogen the ability to connect to cellular integrins and to trigger internalization into host cells. Recent work has highlighted the role of host cell invasion in the pathogenesis of S. aureus, the structure-function relationship of FnBPs, and the host factors required to allow bacterial uptake. Understanding the invasive capacity of S. aureus should open up new avenues to control this microorganism in diverse disease settings.