Cattle mastitis continues to be a global burden for the dairy industry, and its control depends on preventive measures, rapid detection and identification of involved pathogens and accurate antimicrobial treatment. The (mis)use of antimicrobials initiated a rapid evolutionary process of bacterial resistance by natural selection and led to the increased frequency and spread of bacterial antimicrobial resistance (AMR). The global AMR emergency and the prudent use of antimicrobials in cows have raised questions about alternative treatment approaches; however, the use of antimicrobials remains the principal method for mastitis therapy. This chapter summarise the current knowledge on AMR in cattle mastitis as a multifactorial global problem, the trends in AMR patterns in the most common mastitis-causing bacterial pathogens and altering factors, the policies and actions restricting the use of antimicrobials in cows and related challenges in the treatment. The reasons influencing the outcome of treating an intramammary infection, such as the selection of appropriate antimicrobial agents, optimal drug regimens, the gaps in antimicrobial susceptibility testing (AST) of mastitis pathogens and interpretation criteria, and the paradoxical relationship between antimicrobial in vitro activity and in vivo efficacy are discussed. The importance of effective mastitis control programmes is emphasised by an overview of (accurate) diagnosis, the evaluation of the therapy, cow health control and farm management practices.