An in-depth understanding of the molecular mechanisms that underpin the host response to infection can pave the way for immunomodulatory therapies. In this thesis we investigated the host response to infection in several molecular layers, seeking to describe and understand the biology that drives the pathophysiology of pneumonia. Most of this work was performed on samples from patients admitted to the hospital with either viral or bacterial community-acquired pneumonia (CAP), either on the ward or on the ICU. We studied circulating immune cells, epithelial cells, platelets, blood plasma and bronchoalveolar fluids. Within these biological substrates, we sought to understand the pathophysiology of infection in multiple molecular layers: RNA, proteins, metabolites and lipids. This work has helped delineate shared and distinct immune features between different aetiologies of CAP, mapped the immunological response during CAP at the single-cell level, pushed the scientific boundaries regarding cellular lipidomics, and encouraged the field of sepsis research to start embracing complexity. Overall, this work contributes to a better understanding of the physiology underpinning the host response during infection, which can ultimately translate into novel diagnostic and therapeutic strategies that enhance patient care.