Nasal decolonization of Staphylococcus aureus has been accepted as an established prophylactic therapy to prevent post-operative infection, as colonization with S. aureus or MRSA (Methicillin-resistant Staphylococcus aureus) is now a known independent risk factor linked to increasing incidence and severity of infection after surgery. The principal topical antimicrobial in use today for decolonization (mupirocin) was approved by the US FDA nearly two decades ago for ‘the eradication of nasal colonization with MRSA’ and completed its ‘microbiology review’ in July 1997 for the treatment of small wounds. In the twenty years since its approval for nasal decolonization, there have been ever increasing reports of S. aureus eradication failure and antimicrobial resistance to mupirocin from around the world, including eradication failures with mupirocin susceptible species based solely on biofilm production. This article attempts to cover three aspects of S. aureus nasal decolonization: (a) present a brief history of the data that has established S. aureus in the human nares as a locus for distal infection; (b) do a review of published photo-biologic data showing attenuation of efflux pumps and generic antimicrobial potentiation against MRSA; (c) do an examination of new data concerning the potential benefit of a novel photo-biologic ‘minimum biofilm inhibitory concentration’ of near infrared light (PMBIC). This third aspect will be discussed as a possible pre-treatment for overcoming antimicrobial resistance in MRSA, and restoring a higher efficacy for mupirocin as a nasal decolonization therapy.