Understanding of how the human pathogen Streptococcus pneumoniae perceives and responds to its environment in the host offers insight into the pathogenesis of disease caused by this important bacterium and the potential for improved interventions. A central role in this environmental response is played by two-component systems (TCSs), which both sense the environment and drive the cellular response. Molecular advances in the form of genome sequencing, signature-tagged mutagenesis, differential fluorescence induction and microarray analysis have yielded considerable progress in the study of these systems in S. pneumoniae. These recent advances are discussed here, focusing in particular on the role of TCSs in the virulence of S. pneumoniae.