Most Gram-positive bacteria incorporate membrane- or peptidoglycan-attached carbohydrate-based polymers into their cell envelopes. Such cell-wall glycopolymers (CWGs) often have highly variable structures and have crucial roles in protecting, connecting and controlling the major envelope constituents. Further important roles of CWGs in host-cell adhesion, inflammation and immune activation have also been described in recent years. Identifying and harnessing highly conserved or species-specific structural features of CWGs offers excellent opportunities for developing new antibiotics, vaccines and diagnostics for use in the fight against severe infectious diseases, such as sepsis, pneumonia, anthrax and tuberculosis.