The human major histocompatibility complex includes a group of non-classical HLA class I genes, HLA-E, -F and -G. While nearly all focus since the discovery of these class Ib molecules have been on basic biochemistry and molecular biology of HLA-G and HLA-E, as well as their expression patterns, functions in immune modulation and during pregnancy, and also possible implications in a range of diseases, in infertility and pregnancy complications, HLA-F has nearly been ignored. However, recent discoveries show that HLA-F can be expressed as both open conformers binding to a number of KIRs on primarily NK cells, as well as peptide-bound HLA-F binding to ILT2 and ILT4. Furthermore, a number of reports indicate a possible involvement of HLA-F in viral infections, in cancer immunology, and in fertility and reproduction, which may initiate more interest in this rather unknown HLA class I molecule. In this short review, we focus on recent discoveries that indicate a functional role for HLA-F in reproduction and during pregnancy, and the role of HLA-F in relation to HLA-G.