Publisher Summary Streptococcus pneumoniae (Strep. pneumoniae) is Gram-positive and encapsulated. It is now recognized as a major human pathogen in infancy, childhood, and adult life. Strep. pneumoniae is capable of causing both non-invasive diseases such as otitis media, and invasive infections such as pneumonia, meningitis, and sepsis. The pneumococcal outer surface comprises three main parts: the capsule, cell wall, and the plasma membrane. Virulence factors may be cell associated or be produced as soluble factors. The vaccine has a low efficacy because some groups of patients have poor antibody responses to polysaccharide-based vaccines. Mouse models provide direct evidence that cytokines are involved in the host response to Strep. pneumoniae. The typical Gram-positive cell wall is composed mainly of peptidoglycan (PG) glycan chains of alternating N-acetlyglucosamine and N-acetylmuramic acid. PG is synthesized by a set of enzymes that are the target for the antibiotic penicillin. The genes for the synthesis of phosphorylcholine are located in the pneumococcal genome and mutations in these can be lethal for the pneumococcus.