Recent studies of the nonclassical HLA-G class I gene provide insight into its function(s) during pregnancy. The HLA-G gene can be transcribed in different isoforms resulting from alternative splicings and encoding membrane-bound and soluble proteins. These different mRNA species have been found in the various trophoblast cell subpopulations that constitute the maternofetal interface in the human placenta. The raising of antibodies to HLA-G has introduced new tools to determine in which types of trophoblast cells and in which other tissues these transcriptional isoforms are translated in functional proteins. The HLA-G gene exhibits a certain amount of polymorphism, the exon three that encodes the alpha 2 external domain showing the most extensive nucleotide variability. It remains to be determined whether the homozygosity of some HLA-G alleles constitutes a real disadvantage in terms of pregnancy or resistance to specific pathogens. Regarding the potential antigen-presenting function(s) of HLA-G, two isoforms are capable of binding an identical set of nonamer peptides derived from a variety of intracellular proteins. The ligand motif contains three anchor residues and is similar to that of classical HLA class I molecules. Experiments are being performed to identify the recognizing cells and to determine whether HLA-G induces a cytolytic (including anti-viral) T-cell response or in some other way represses natural killer-cell functions.