The community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) epidemic in the United States is largely attributable to the meteoric rise of a single clone, referred to as USA300. This strain not only spread across the United States in just a few years to become the predominant cause of staphylococcal disease, but it also appears to have increased the overall number of skin and soft-tissue infections (SSTIs), increasing the overall disease burden. While USA300 still constitutes a major public health burden, its prevalence may be decreasing in some parts of the United States. Other than an epidemic in South America due to a closely related strain, USA300 also seems to have been largely unable to establish itself as an endemic infection in other geographic locations. While there have been several hypotheses put forward to explain the enormous success of USA300, the reasons for its failures and its potential fall remain obscure. Far from being unique to USA300, the rise and fall of specific clones of S. aureus in human populations seems to be a common process that has occurred multiple times and in multiple locations. This review charts the rise of USA300 and the evidence that suggests that it may be in decline, and it considers how best to understand the future spread, containment, and possible extinction of CA-MRSA.