The innate immune system detects pathogens and initiates host defences. Canonical detection of pathogens as “non-self” relies on sensing of microbial components, including lipopolysaccharide and nucleic acids, as pathogen-associated molecular patterns (PAMPs) by germline-encoded pattern recognition receptors (PRRs). PRRs activate the immune system to induce inflammation, to recruit and alert immune cells, and to defend against the intruder. Pathogens aim to avoid immune defences leading to a molecular arms race between pathogens and their hosts. We use functional genomics to identify genetic components of host-pathogen interactions, innate immune sensing, and immune homeostasis.