Innate immunity is a pillar of the host’s defense against infection and noxious self. Pathogen or danger recognition systems (PRRs) including TLRs, inflammasomes, and RIG-I-like receptors are broadly recognized as central nodes of innate immune responses and have a solid place in the immunologists’ hearts. The complement system, however, albeit being the evolutionary oldest PRR, is often perceived as the ‘Stiefkind’ of innate immunity and generally evokes less excitement. This view is changing: complement has recently been up-graded from a mere lytic pathogen-killer to an intracellularly-active orchestrator of normal cell physiology. This, together with the realization that an increasing number of human diseases, among those COVID-19, involve complement perturbations has spurred a regained interest in complement biology and its therapeutic targeting. Our knowledge, however, of how complement exerts non-canonical activities and how it intersects with other PRRs is sparse. This conference will provide a timely account of recent paradigm shifts in our understanding of complement/PRR-instructed immunity with a specific eye on emerging roles in basic cellular processes including regulation of chromatin structure, metabolism, cell death, clearance of cellular debris/corpses, and maintenance of normal CNS function. A second focus is on exploring how aberrant function of these new PRR activities contribute to infection and autoimmunity but also to less intuitive clinical conditions like changes in cognition and behavior. This holistic and ‘complement-inclusive’ vantage-point on PRR biology brings together interdisciplinary investigators from academia and industry for cross-fertilization of novel ideas and collaborations towards biomedical progress in harnessing complement to combat human disease.