HLA-E, HLA-F, and HLA-G are human nonclassical MHC class Ib molecules. To study the function and identify potential ligands of these molecules, we constructed tetrameric complexes. In this brief review, we discuss the methods used to produce such tetramers and the interesting results they provided. HLA-E tetramers bound to natural killer (NK) cells and T cells, allowing the identification of CD94/NKG2 molecules as receptors for HLA-E. HLA-G tetramers interacted with immunoglobulin-like transcript-2 (ILT2) and ILT4 receptors, aiding the understanding of HLA-G function during pregnancy. Tetrameric complexes of HLA-F also bound to ILT2 and ILT4.