Staphylococcus aureus is a commensal of the skin and nares of humans as well as the causative agent of infections associated with significant mortality. The acquisition of antibiotic resistance traits complicates the treatment of such infections and has prompted the development of monoclonal antibodies. The selection of protective antigens is typically guided by studying the natural antibody responses to a pathogen. What happens when the pathogen masks these antigens and subverts adaptive responses, or when the pathogen inhibits or alters the effector functions of antibodies? S. aureus is constantly exposed to its human host and has evolved all these strategies. Here, we review how anti- S. aureus targets have been selected and how antibodies have been engineered to overcome the formidable immune evasive activities of this pathogen. We discuss the prospects of antibody-based therapeutics in the context of disease severity, immune competence, and history of past infections.