Because the availability of fish genomic data, the number of reported sequences for fish type II helical cytokines is rapidly growing, featuring different IFNs including virus-induced IFNs (IFN_) and IFN-_, and IL-10 with its related cytokines (IL-20, IL-22, and IL-26). Many candidate receptors exist for these cytokines and various authors have postulated which receptor chain would be involved in which functional receptor in fish. To date, only the receptor for zebrafish IFN_1 has been identified functionally. Three genes encoding virus-induced IFN_s have been reported in zebrafish. In addition to these genes clustered on chromosome 3, we have identified a fourth IFN_ gene on chromosome 12. All these genes possess the intron-exon organization of mammalian _ IFNs. In the zebrafish larva, all induce the expression of reporter antiviral genes; protection in a viral challenge assay was observed for IFN_1 and IFN_2. Using a combination of gain- and loss-of-function experiments, we also show that all zebrafish IFN_s do not bind to the same receptor. Two subgroups of fish virus-induced IFNs have been defined based on conserved cysteines, and we find that this subdivision correlates with receptor usage. Both receptor complexes include a common short chain receptor (CRFB5) and a specific long chain receptor (CRFB1 or CRFB2).