**Abstract**

*Staphylococcus aureus* is a notorious human pathogen that causes superficial and invasive infections both in nosocomial and community-acquired settings. The prevalence of staphylococcal infections became more challenging after emerging resistance against topical antibiotics. *S. aureus* evolved resistance to β-lactam antibiotics due to modification and expression of penicillin-binding proteins (PBP), inactivation of drug by β-lactamase synthesis, limiting uptake of drug by biofilm formation, and reducing uptake by expression of efflux pump. The wave of resistance was first observed in penicillin by β-lactamase production and PBPs modification. The second wave of resistance emerged to methicillin by appearing methicillin-resistant *S. aureus* (MRSA) strains. Cephalosporin has long been used as the last resort for preventing MRSA infections, but resistant strains appeared during treatment. In progression to control MRSA or related infections, carbapenems have been used but strains developed resistance. *S. aureus* is among the high-priority resistance organisms that need renewed efforts for the research and development of new antibiotics and innovative preventive approaches. However, a lot of toiling is involved in devising an effective treatment against drug resistant *S. aureus*. This chapter aim is to retrospectively determine the progression of resistance in *S. aureus*, against different β-lactam antibiotics and their challenges of medication.

**Keywords:** *Staphylococcus aureus*, Drug resistance, β-lactam antibiotics, Penicillin, Methicillin, Cephalosporin
