All multicellular organisms protect themselves against pathogens using sophisticated immune defenses. Functionally interconnected humoral and cellular facilities maintain immune homeostasis in the absence of overt infection and regulate the initiation and termination of immune responses directed against pathogens. Immune responses of invertebrates, such as flies, are innate and usually stereotyped; those of vertebrates, encompassing species as diverse as jawless fish and humans, are additionally adaptive, enabling more rapid and efficient immune reactivity upon repeated encounters with a pathogen. Many of the attributes historically defining innate and adaptive immunity are in fact common to both, blurring their functional distinction and emphasizing shared ancestry and co-evolution. These findings provide indications of the evolutionary forces underlying the origin of somatic diversification of antigen receptors and contribute to our understanding of the complex phenotypes of human immune disorders. Moreover, informed by phylogenetic considerations and inspired by improved knowledge of functional networks, new avenues emerge for innovative therapeutic strategies.