Staphylococcus aureus causes infections ranging from superficial wound infections to life-threatening systemic infections. Essential for S. aureus pathogenicity are a number of cell-wall-associated and secreted proteins that are controlled by a complex regulatory network involving the quorum-sensing agr locus and a large set of transcription factors belonging to the Sar family. Recently, we revealed a new layer of regulation by showing that mutants lacking the ClpXP protease produce reduced amounts of several extracellular virulence factors and that, independently of ClpP, ClpX is required for transcription of spa, encoding Protein A. Here we find that the independent effect of ClpX is not general for other cell wall proteins, as expression of fibronectin- and fibrinogen-binding proteins was increased in the absence of either ClpX or ClpP. To assess the roles of ClpX and ClpP within the sar/agr regulatory network, deletions in clpX and clpP were combined with mutations in these genes. Interestingly, the derepression of spa transcription normally observed in an agr-negative strain was abolished in cells devoid of ClpX, and apparently ClpX modulates both SarS-dependent and SarS-independent control of spa expression, perhaps through the Sar family member Rot. Examination of expression of a single secreted protein, the SspA serine protease, revealed that ClpXP, similar to agr, is required for growth phase-dependent transcriptional induction of sspa. Intriguingly, induction was restored by the concomitant inactivation of Rot. We hypothesize that RNAIII accumulating in the postexponential phase may target Rot for degradation by ClpXP, leading to derepression of sspA.