Background: The rising prevalence of the antibiotic-resistant strains of Staphylococcus aureus, notably to the Methicillin-resistant Staphylococcus aureus (MRSA), presents a critical challenge in contemporary healthcare. By examining the unique challenges posed by antibiotic-resistant strains, we underscore the urgent need for innovative therapeutic interventions. The review navigates the current landscape of antibiotic development, focusing on the exploitation of membrane proteins as viable targets for drug design. Membrane proteins in S. aureus, including adhesins, transporters, and signal transduction proteins, are dissected for their contributions to bacterial pathogenicity and resilience. The article elucidates the interplay between membrane proteins and antibiotic resistance, offering insights into the potential vulnerabilities that can be harnessed for drug development. Drawing attention to the multifaceted nature of membrane proteins, we discuss their critical roles in biofilm formation, nutrient acquisition, and evasion of host defences, underscoring their significance as druggable targets. In conclusion, this review critically examines the prospects and challenges of membrane protein-driven drug development in Staphylococcus aureus, highlighting the promising avenues for bridging the gap in antibiotic efficacy against resistant strains. The comprehensive exploration of this paradigm aims to inform and inspire researchers in the pursuit of innovative strategies to mitigate the looming threat to the antibiotic resistance in one of the most clinically significant bacterial pathogens. © 2024 Elsevier B.V., All rights reserved.