For 100 y, the study of the molecular mechanism of pneumococcal infection has richly rewarded biomedical science and pediatrics. More recently, a framework has emerged for how the pathogen engineers colonization, invasion of the lung and bloodstream, and finally, entry into the brain. This trafficking is then followed by a separate set of events to generate the symptoms of disease. Understanding the ligand receptor interactions that dictate these events has suggested new concepts for how to control the course of an infectious process and improve the morbidity and mortality of encounters with this prevalent pathogen of children.