PURPOSE OF REVIEW: Studying primary immunodeficiencies (PIDs) provides insights into human antiviral immunity in the natural infectious environment. This review describes new PIDs with genetic defects that impair innate antiviral responses. RECENT FINDINGS: New genetic defects in the interferon (IFN) signaling pathway include IFNAR1 deficiency, which causes uncontrolled infections with measles-mumps-rubella or yellow fever vaccines, and possibly also cytomegalovirus (CMV); and IRF9 deficiency, which results in influenza virus susceptibility. Genetic defects in several pattern recognition receptors include MDA5 deficiency, which impairs viral RNA sensing and confers human rhinovirus susceptibility; RNA polymerase III haploinsufficiency, which impairs sensing of A:T-rich virus DNA and confers VZV susceptibility; and TLR3 deficiency, which causes HSV-1 encephalitis (HSE) or influenza virus pneumonitis. Defects in RNA metabolism, such as that caused by Debranching enzyme 1 deficiency, can cause virus meningoencephalitis. Finally, defects in host restriction factors for virus replication, such as in CIB1 deficiency, contribute to uncontrolled beta-HPV infections. SUMMARY: Several new PIDs highlight the role of type I/III IFN signaling pathway, virus sensors, and host virus restriction factors in human antiviral immunity.