Streptococcal species are a diverse group of bacteria which can be found in animals and humans. Their interactions with host organisms can vary from commensal to pathogenic. Many of the pathogenic species are causative agents of severe, invasive infections in their hosts, accounting for a high burden of morbidity and mortality, associated with high economic costs in industry and health care. Among them, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus pneumoniae, and Streptococcus suis are discussed here. An environmentally stimulated and tightly controlled expression of their virulence factors is of utmost importance for their pathogenic potential. Thus, the most universal and widespread regulators from the classes of stand-alone transcriptional regulators, two-component signal transduction systems (TCS), eukaryotic-like serine/threonine kinases, and small noncoding RNAs are the topic of this chapter. The regulatory levels are reviewed with respect to function, activity, and their role in pathogenesis. Understanding of and interfering with transcriptional regulation mechanisms and networks is a promising basis for the development of novel anti-infective therapies.