Staphylococcal antimicrobial resistance presents an emerging challenge for both human and veterinary medical professionals. Infections associated with methicillin- and multidrug-resistant staphylococci are increasingly encountered by veterinarians and are frequently associated with empiric therapeutic failures and limited systemic antimicrobial options. This article addresses mechanisms of antimicrobial resistance in common staphylococcal pathogens and implications for clinical practice, including indications for culture and susceptibility testing, rational antimicrobial selection, and potential for zoonotic transmission.