Pneumococcus remains the most common cause of community-acquired pneumonia worldwide. Streptococcus pneumoniae is well adapted to people, and is a frequent inhabitant of the upper airways in healthy hosts. This seemingly innocuous state of colonisation is a dynamic and competitive process in which the pathogen attempts to engage the host, proliferate, and invade the lower airways. The host in turn continuously deploys an array of innate and acquired cellular and humoral defences to prevent pneumococci from breaching tissue barriers. Discoveries into essential molecular mechanisms used by pneumococci to evade host-sensing systems that are designed to contain the pathogen provide new insights into potential treatment options. Versatility of the genome of pneumococci and the bacteria's polygenic virulence capabilities show that a multifaceted approach with many vaccine antigens, antibiotic combinations, and immunoadjuvant therapies will be needed to control this microbe.