© 2015 Elsevier Inc. All rights reserved. Streptococcus pneumoniae (the pneumococcus) is a medically important opportunistic pathogen. Serious disease, such as pneumonia and invasive infections, typically occurs in individuals who are at the extremes of age and/or in those who are immunocompromised. In these individuals, and during the less common infection of otherwise healthy young adults, pneumococcal disease frequently develops as the result of a preceding viral infection that skews the host response. This chapter reviews the molecular mechanisms that underlie susceptibility to pneumococcal infection. We discuss the susceptibility of infants to invasive disease, genetic mutations that specifically lead to enhanced vulnerability to the pneumococcus, reasons for the inability of the elderly to adequately respond to S. pneumoniae both in the innate and adaptive arms of the immune system, and how HIV and influenza enhance susceptibility to pneumococcal colonization, augment disease severity, and facilitate S. pneumoniae transmission to a naïve host.