Staphylococcus aureus is the primary etiological agent of several human diseases. S. aureus has classically been considered an extracellular pathogen; however, recent evidence indicates that S. aureus invades and persists in non-professional phagocytes. Experiments demonstrate that actin microfilaments, microtubules, receptor-mediated endocytosis, and protein tyrosine kinases play important roles in the uptake of S. aureus. Fibronectin-binding proteins and beta-integrins are implicated as critical cell surface molecules associated with internalization of S. aureus by non-phagocytic cells. Following invasion of eukaryotic cells, S. aureus induces the release of cytokines that have the potential to exacerbate disease and induce apoptosis. Finally, S. aureus has the ability to persist inside host cells as small colony variants, a phenotype associated with persistent and recurrent infections.