Interferons (IFNs) manifest their cellular functions by regulating expression of target genes known collectively as IFN-stimulated genes (ISGs). The repertoires of ISGs vary slightly between cell types, but routinely include a core of common ISGs robustly upregulated in most IFN-treated cells. Here, we review the regulation and cellular functions of 2 related ISGs, ISG12 (IFI27) and G1P3 (ISG 6–16), that are commonly induced by IFNs in most, if not all, IFN-responsive cells. On the basis of sequence similarity, they are grouped together within the newly defined FAM14 family. Emerging data on ISG12 and G1P3 suggest that both are mitochondrial proteins with opposing activities on apoptosis that may influence the innate immune responses of IFNs. The G1P3 gene encodes a low molecular weight mitochondrial protein that may stabilize mitochondrial function and oppose apoptosis. In contrast, ISG12 expression may sensitize cells to apoptotic stimuli via mitochondrial membrane destabilization. On the basis of these results and differences in induction kinetics between ISG12 and G1P3, we have proposed a model for the role of these genes in mediating cellular activity of IFNs.