Major histocompatibility complex (MHC) class I molecules function to present pathogen-derived peptides to cytotoxic T cells or act as ligands for Natural Killer cells, thus alerting the immune system to the presence of invading pathogens. Furthermore MHC class I molecules can be strongly associated with autoimmune diseases. Therefore understanding not only the biosynthesis and the degradation pathways of MHC class I molecules has become important in determining their role in pathogen and autoimmune-related diseases. Here we describe how using epitope-tagged MHC class I molecules can aid in the analysis of MHC class I molecule biosynthesis and degradation and also complement studies using conventional conformationally specific antibodies. Coupled together with pharmacological manipulation which can target both biosynthetic and degradative pathways, this offers a powerful tool in analyzing MHC class I molecules.