Staphylococcus aureus is the leading cause of hospital-acquired infections and can cause a wide range of diseases from mild skin infections to invasive diseases including deep surgical site infections, life-threatening bacteremia, and sepsis. This pathogen remains a challenge to manage due to its ability to rapidly develop resistance to antibiotic treatment and to form biofilms. Despite the current infection control measures which involve mainly antibiotics, the burden of infection remains high. The ‘omics’ approaches have not led to the discovery of novel antibacterials at a pace sufficient to cope with the emergence of multidrug-resistant and biofilm-forming S. aureus, Hence, new strategies for anti-infective therapies need to be explored urgently. One promising strategy is harnessing the immune response to enhance the protective antimicrobial immunity in the host. This review discusses the potential of monoclonal antibodies and vaccines as alternatives to treat and manage infections caused by planktonic and biofilms of S. aureus.© The Author(s) 2023. Published by Oxford University Press on behalf of FEMS.