Recently, the use of invertebrate models of infection has given exciting insights into host-pathogen interaction for a number of bacteria. In particular, this has revealed important factors of the host response with remarkable parallels in higher organisms. Here, we review the advances attained in the elucidation of virulence determinants of a major human pathogen, Staphylococcus aureus, in relation to the invertebrate models thus far applied, the silkworm (Bombyx mori), the fruit fly (Drosophila melanogaster) and the roundworm (Caenorhabditis elegans). Also, the major pathways of host defence are covered in light of the response to S. aureus and the similarities and divergences in innate immunity of vertebrates and invertebrates. Consequently, we comparatively consider pathogen recognition receptors, signal transduction pathways (including Toll, Imd and others), and the humoral and cellular antimicrobial effectors. The technically convenient and ethically acceptable invertebrates appear as a valuable first tool to discriminate molecules participating from both sides of the host-S. aureus interaction as well as a high throughput method for antimicrobial screening.