Recent studies make evident that innate immune defense mechanisms are more specific than have classically been appreciated. Molecular recognition systems and antimicrobial effector molecules have been optimized by evolutionary time to defend cognate anatomic, physiologic, and microbiologic microenvironments upon and/or within the host. Consequently, host defense peptides are now viewed as having context-relativity pertaining to target organisms, conditional optima, or mechanisms of action versus resistance. In addition, many peptides exert functions to bridge innate and adaptive immunity. Collectively, these relationships comprise the concept of immunorelativity. Several lines of evidence illustrate how such themes apply to host defense peptide responses to Staphylococcus aureus. Distinct repertoires of polypeptides with activity against S. aureus exist in epidermal, mucosal, or bloodstream contexts. Likewise, physiologic parameters such as pH, ionic and osmotic tone differ among these contexts, and impact the biophysical properties of peptides, as well as the status of the target organisms. These factors contribute to net S. aureus susceptibility or resistance to such peptides, and therefore influence host defense against infection by this omnipresent organism.