Interferon epsilon (IFNɛ) is a type I interferon, first identified in the female reproductive tract of gestating mice in 2004 (1). Unlike other type I interferons, IFNɛ expression is not induced by pathogen-associated molecular patterns (PAMPs), but rather is upregulated by estrogen and downregulated by progesterone (2). It is selectively and constitutively expressed in the female reproductive tract and is known to perform anti-viral and anti-inflammatory roles in other mucosal sites, such as the respiratory and gastrointestinal tracts (3)(4). We hypothesise that IFNɛ may have a divergent function in the reproductive tract during pregnancy, acting as an anti-inflammatory protector of the semi-allogeneic foetus and placenta. We further propose indications that IFNɛ is absent in mammals lacking a chorio-allantoic placenta (marsupials and monotremes), perhaps consistent with lineage-specific gene duplication and loss events within the type I interferon family. We use sequence homology searches to identify IFNE gene homologues and to define their phylogenetic distribution across mammals. Evolutionary selection pressures on IFNɛ are analysed to question correlations with the emergence of placental structures. Promoter regions from representative mammalian species are examined to identify regulatory elements underlying the unique expression pattern of IFNɛ relative to other type I interferons in the same gene cluster. These analyses provide insights into the evolution and specialised function of IFNɛ, with implications for reproductive tract immunity, infection and infertility.