Despite advances in its management, community-acquired pneumonia (CAP) remains the most important cause of sepsis-related mortality and the reason for many ICU admissions. Severity assessment is the cornerstone of CAP patient management and the attempts to ensure the best site of care and therapy. Survival depends on a combination of host factors (genetic, age, comorbidities, defenses), pathogens (virulence, serotypes) and drugs. To reduce CAP mortality, early adequate antibiotic therapy is fundamental. The use of combination therapy with a macrolide seems to improve the clinical outcome in the subset of patients with high inflammation due to immunomodulation. Guidelines on antibiotic therapy have been associated with beneficial effects, and studies of newer adjunctive drugs have produced promising results. This paper discusses the current state of knowledge regarding of precision medicine and the treatment of severe CAP patients.