Global regulation of virulence gene expression via transcriptional regulators plays a central role in the ability of the bacterial pathogen Streptococcus pyogenes (the group A Streptococcus, GAS) to rapidly adapt during infection. The ‘stand-alone’ regulators Mga, RofA-like proteins (RALPs), and RopB/Rgg control important and diverse virulence regulons in response to growth-related signals and other environmental conditions in GAS. Stand-alone regulated genes encode factors important for colonization of tissues, immune evasion, persistence, dissemination, metabolism, and the response to stressors. Although conserved ‘core’ regulons have been established for each, recent studies have revealed significant inter-serotype and even intra-serotype variation in the regulatory patterns presented by the stand-alone regulators. This chapter will look at each stand-alone regulatory pathway in depth and discuss how these important global networks influence virulence as well as interact with each other to produce an integrated response during GAS infection.