Streptococcus pneumoniae is responsible for two-thirds of ICU admissions due to community-acquired pneumonia (CAP) and is the leading cause of CAP-related death. Early death is principally due to cardiovascular collapse, whereas late death is associated with hypoxemic respiratory failure. Outcome depends on interactions between non-modifiable factors of predisposition (age, comorbidities, host defences, genetic predisposition) or infection (toxins, virulence, bacterial burden) and modifiable factors (organ-failure support, surgical drainage for empyema, adjuvant therapies and antibiotics). Excess mortality has been reported when initial therapy is discordant, but more than 95% of isolates have minimum inhibitory concentration (MIC) <4 microg/ml. Therefore, cefotaxime, ceftriaxone and high doses of amoxicillin remain successful for non-meningeal infections. Recent studies suggest that initial combination therapy improves survival in the subset of bacteremic episodes with highest severity, conceivably due to the immunomodulatory effects of macrolides. Prospective, randomized clinical trials of pneumonia patients with a pneumonia severity index score above 90 are warranted to define optimal antibiotic regimens.