Background: Methicillin resistant S. aureus (MRSA) has been declining over the past decade, but changes in S. aureus overall and the implications for trends in antibiotic resistance remain unclear. Objective: To determine whether the decline in rates of infection by MRSA has been accompanied by changes in rates of infection by methicillin susceptible, penicillin resistant S. aureus (MSSA) and penicillin susceptible S. aureus (PSSA). We test if these dynamics are associated with specific genetic lineages and evaluate gains and losses of resistance at the strain level. Methods: We conducted a 15 year retrospective observational study at two tertiary care institutions in Boston, MA of 31,589 adult inpatients with S. aureus infections. Surveillance swabs and duplicate specimens were excluded. We also sequenced a sample of contemporary isolates (n = 180) obtained between January 2016 and July 2016. We determined changes in the annual rates of infection per 1,000 inpatient admissions by S. aureus subtype and in the annual mean antibiotic resistance by subtype. We performed phylogenetic analysis to generate a population structure and infer gain and loss of the genetic determinants of resistance. Results: Of the 43,954 S. aureus infections over the study period, 21,779 were MRSA, 17,565 MSSA and 4,610 PSSA. After multivariate adjustment, annual rates of infection by S. aureus declined from 2003 to 2014 by 2.9% (95% CI, 1.6%-4.3%), attributable to an annual decline in MRSA of 9.1% (95% CI, 6.3%-11.9%) and in MSSA by 2.2% (95% CI, 0.4%-4.0%). PSSA increased over this time period by 4.6% (95% CI, 3.0%-6.3%) annually. Resistance in S. aureus decreased from 2000 to 2014 by 0.86 antibiotics (95% CI, 0.81-0.91). By phylogenetic inference, 5/35 MSSA and 2/20 PSSA isolates in the common MRSA lineages ST5/USA100 and ST8/USA300 arose from the loss of genes conferring resistance. Conclusions and relevance: At two large tertiary care centers in Boston, MA, S. aureus infections have decreased in rate and have become more susceptible to antibiotics, with a rise in PSSA making penicillin an increasingly viable and important treatment option.