Regulatory mechanisms for chromosomal genes encoding multidrug resistance (MDR) efflux pumps (EPs) in Staphylococcus aureus are poorly defined. Microbiological, quantitative gene expression, mRNA half-life and genome data for 11 strains of S. aureus combined with bioinformatic analyses were used to identify correlates of increased MDR EP gene expression. The presence of qacA/B and/or increased expression of one to two MDR EP genes were identified in eight strains. Microbiological and gene expression data correlated in four instances, existing knowledge of the substrate specificity of NorC resulted in correlation in two others, and a transcriptional/translational disconnect is possible for the remaining two. In silico analyses and mRNA half-life determinations linked insertions of nucleotide repeats 3′ to the −10 motif of the norA promoter with increased promoter activity. Mutations in the 5′-untranslated and/or coding regions were identified that may affect transcription efficiency. Substitutions of residues in the helix-turn-helix (HTH) motif of NorG may augment its positive regulation of norB. The correlations proposed provide a guide for further experimentation leading to a better understanding of MDR EP gene expression in this important pathogen.