Streptococcus pyogenes is an exclusively human pathogen. Streptococcal attachment to and entry into epithelial cells is a prerequisite for a successful infection of the human host and requires adhesins. Here, we demonstrate that the multidomain protein Epf from S. pyogenes serotype M49 is a streptococcal adhesin. An epf--deficient mutant showed significantly decreased adhesion to and internalisation into human keratinocytes. Cell adhesion is mediated by the N-terminal domain of Epf (EpfN) and increased by the human plasma protein plasminogen. The crystal structure of EpfN, solved at 1.6 A resolution, shows that it consists of two subdomains, a carbohydrate-binding module and a fibronectin type III domain. Both fold types commonly participate in ligand-receptor and protein-protein interactions. EpfN is followed by 18 repeats of a domain classified as Domain of Unknown Function 1542 (DUF1542) and a C-terminal cell wall sorting signal. The DUF1542 repeats are not involved in adhesion, but biophysical studies show they are predominantly alpha-helical and form a fibre-like stalk of tandem DUF1542 domains. Epf thus conforms with the widespread family of adhesins known as MSCRAMMs (microbial surface components recognizing adhesive matrix molecules), in which a cell wall-attached stalk enables long-range interactions via its adhesive N-terminal domain.