Streptococcus pyogenes is an important human pathogen that can cause a variety of diseases in immunocompetent individuals ranging from uncomplicated superficial infections to severe life-threatening infections including rapidly progressing deep tissue infections, such as necrotizing fasciitis (NF) and severe cellulitis. The pathogenesis of these infections is complex and multifactorial involving numerous virulence factors expressed by the bacteria. Here, we review data from epidemiologic, pathogenomic, and pathogenesis studies that have provided insight into the host-pathogen interactions that contribute to S. pyogenes tissue infections. The role of tissue-specific streptococcal types, intracellular bacterial persistence, and other immune evasion strategies resulting in massive bacterial load at the tissue site, as well as virulence factors contributing to a local hyperinflammatory response are highlighted. A particular focus is on in vivo findings in patients that provide insight into host and bacterial factors that are expressed at the infected tissue site, and the mechanisms underlying tissue pathology.