Successful pregnancy includes remodeling and differentiation of the endometrium in response to sex steroid hormones, development of maternal immunotolerance to the implanting embryo, and modification of the local uterine environment by the embryo to suit its own needs. The major signal released by the ruminant conceptus during establishment of pregnancy is interferon-tau (IFNT) that stimulates the expression of many genes in the endometrium and ovary. One of these genes is called interferon stimulated gene 15 (ISG15), which encodes a ubiquitin homolog with a C-terminal Gly that becomes covalently attached to Lys residues on targeted proteins through an ATP-dependent multi-step enzymatic reaction called ISGylation. The conceptus-derived induction of endometrial ISGs also occurs in mouse and human deciduas and placenta, in response to pregnancy presumably through action of cytokines such as interleukins and type I IFN. Described herein is evidence to support the concept that ISGylation is a maternal response to the developing conceptus, implantation and placentation that is conserved across mammalian pregnancy. Although the precise role for ISG15 remains elusive during pregnancy, it is clear that up-regulation in response to pregnancy may impart a pre-emptive defense to infection or other environmental insults, and protection of the conceptus against inflammatory insults across species.