Staphylococcus (S.) aureus is a leading cause of hospital and community acquired infections. Strains of methicillin resistant S. aureus (MRSA) have emerged that are resistant to all but a few antibiotics, raising the specter of untreatable disease. Indicative of its medical importance, considerable data has been collected on S. aureus, including the whole genomic sequences of several strains with different resistance phenotypes, a diversity of transcriptome data, and a vast assortment of documented observations concerning the characteristics of mutants. These various types of data were analyzed to identify determinants of resistance to four types of clinically important antibacterial agents rifampin, beta-lactams, vancomycin, and daptomycin that target respectively RNA polymerase, key cell wall synthesis enzymes, a fundamental cell wall precursor, and the cytoplasmic membrane. To elucidate regulatory networks, statistically over-represented patterns representing the binding sites of transcription factors were searched for in genomic sequences. To discover mechanisms of resistance, isogenic isolates displaying progressively increasing levels of resistance were sequenced using the method of whole genome shotgun sequencing. By consulting the large body of literature on S. aureus, it was possible to correlate observed genetic changes with transcriptome and phenotypic changes using various statistical methods. The identified determinants of resistance and their potentially complex pleitropic effects are discussed in some detail.