Living things in all domains of life have evolved innate immune systems to protect against diverse infectious agents and maintain homeostasis. We still lack a fundamental understanding on how the innate immune system is activated to elicit protective responses, and how it can also overreact to certain insults to harm self. This Keystone meeting aspires to bring together those interested in innate immunity in all its diverse forms. We seek insights into the diversity of innate immune mechanisms, the deep evolutionary origins of innate immunity, the important roles of innate immunity in human disease, and its indispensable function in shaping adaptive immune responses to infections and cancer. The sessions will span those working at multiple levels, from molecular structures to cellular interactions, and to organismal biology and human pathology. We expect cross-disciplinary interactions to fertilize novel insights into the innate immune system, from innate sensing to adaptive responses. This conference will be jointly held with the Vaccinology Keystone meeting. Since the innate immune system is the source of key signals required for vaccines to elicit adaptive responses, we anticipate the two meetings will be highly synergistic.