Although S. pneumoniae (Spn) has been investigated for over a century, it is still a major human pathogen that causes a variety of invasive pneumococcal diseases (IPDs) such as pneumonia, otitis media, bacteremia, and meningitis. Spn can be divided into over 100 serotypes based on the structural differences of their capsular polysaccharides (CPSs). Since the introduction of the 13-valent (PCV13) glycoconjugate vaccines, effective against the most prevalent serotypes, the incidence rates of IPDs in children have been greatly reduced, with limited effects on morbidity in elderly and immunocompromised populations. Despite a global vaccination program and the use of antibiotics, Spn remains among the deadliest infectious agents worldwide. Widespread use of antibiotics as therapeutics has led to the spread of drug resistant pneumococcal strains. We hypothesized that previously-characterized and novel pneumococcal surface glycans play important roles in bacterial virulence and its interactions with the host. We also hypothesized that exploiting these surface molecules for immune recognition may address the shortcomings of the incumbent vaccination and antibiotic regimen and offer potent prophylactic and therapeutic approaches to reduce the burden of IPDs. In this dissertation, we provide evidence for the functional roles of Spn serotype 3 CPS-specific CD4+ T cells. We also identified and characterized a serotype 3 CPS degrading enzyme (Pn3Pase) that proves to be protective against serotype 3 Spn in colonization and infection models. Additionally, we show that several glycosyltransferases that modify pneumococcal serine rich protein (PsrP) are critical for Spn virulence. Finally, We characterized the glycosylation of pneumococcal surface protein A (PspA) and demonstrated how this glycan modification contributes to immunogenicity and antigenicity of the protein. These studies increase our understanding of the interactions of pneumococcal surface glycans with the host and may lead to new treatments and vaccines against this highly virulent human pathogen to reduce the burden of IPDs.