Summary: Interferon (IFN) was originally identified as a substance ‘interfering’ with viral replication in vitro. The first IFNs to be identified were classified as type I IFNs (IFN-α/β and related molecules), two other types have since been identified: type II IFN (IFN-γ) and type III IFNs (IFN-λ). Each IFN binds to one of three type-specific receptors. In the mouse model of experimental infections in vivo, IFN-α/β are essential for immunity to most viruses tested, whereas IFN-γ is important for immunity to a smaller number of viruses, together with bacteria, fungi, and parasites, consistent with IFN-γ acting as the ‘macrophage activating factor.’ The precise role of IFN-λ remains unclear. In recent years, inborn errors affecting the production of, or the response to, IFNs have been reported in human patients, shedding light onto the function of IFNs in natura. Disorders of IFN-γ production, caused by IL12B, IL12RB1, and specific NEMO mutations, or of IFN-γ responses, caused by IFNGR1, IFNGR2, and dominant STAT1 mutations, confer predisposition to mycobacterial disease in patients resistant to most viruses. By contrast, disorders of IFN-α/β and IFN-λ production, caused by UNC93B1 and TLR3 mutations, confer predisposition to herpes simplex encephalitis (HSE) in otherwise healthy patients. Consistently, patients with impaired responses to IFN-α/β, IFN-γ, and presumably IFN-λ (carrying recessive mutations in STAT1), or with impaired responses to IFN-α/β and impaired IFN-γ production (carrying mutations in TYK2), or with impaired production of IFN-α/β, IFN-γ, and IFN-λ (carrying specific mutations in NEMO), are vulnerable to mycobacterial and viral infections, including HSE. These experiments of nature suggest that the three types of IFNs play at least two different roles in host defense. IFN-γ is essential for anti-mycobacterial immunity, whereas IFN-α/β and IFN-λ are essential for anti-viral immunity. Future studies in humans aim to define the specific roles of IFN-α/β and IFN-λ types and individual molecules in host defense in natura.