Methicillin-susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) have few structural differences, but their epidemiologies differ profoundly in terms of colonization, infection, and transmission. We compare strategies for controlling hospital infection due to MSSA and MRSA. Despite the straightforward epidemiology of MSSA, the effectiveness of screening and decolonization was established only recently. The optimal strategy for controlling MRSA spread and infection remains debated. Many data need to be acquired, given the complexity of MRSA epidemiology, the entanglement between collective and individual objectives, and the challenges faced when adjusting for confounders. However, studies have consistently demonstrated that screening is useful in high-risk units to identify the reservoir and to initiate contact precautions. In an endemic setting, the contribution of MRSA decolonization to cross-transmission limitation is probably small in comparison to the impact of precautions. Screening and decolonization may be effective in decreasing the MRSA infection risk in carriers.