Streptococcus pyogenes (group A streptococci, GAS) is an important and exclusively human pathogen. Adherence to and internalization into host cells significantly contributes to the pathogenesis of GAS infections. The adherence mechanism is a two-step process in which host extracellular matrix (ECM) proteins act as prime targets. GAS may express more than a dozen different microbial surface components recognizing adhesive matrix molecules (MSCRAMMs) that attach to fibronectin or collagen. One of them, protein F1/SfbI binds fibronectin and mediates adherence of GAS to host cells. Bound fibronectin acts as a bridging molecule towards host cell integrins, which in turn initialize the uptake process that leads to GAS internalization. In their safe intracellular niche GAS can persist protected from antibiotics and host defense, a scenario currently discussed in the context of treatment failure, asymptomatic GAS carriers and recurrent GAS infections. Patients with such low grade infections represent the main GAS reservoir from which the bacteria are spread in the general population. Due to their important function, expression of GAS MSCRAMMs is under control of several "stand alone" transcriptional regulators and two-component signal transduction systems. Several regulator genes are organized together with MSCRAMM genes on one of two potential pathogenicity islands, act together in a growth phase-dependent regulatory network and are expressed in a strain-specific manner. A detailed understanding of these mechanisms is crucial, since interference with MSCRAMM function alone or in conjunction with specific manipulations of regulators is an attractive goal for novel anti-infective strategies.