Major histocompatibility complex (MHC) class I molecules function to present pathogen derived peptides to cytotoxic T cells and act as ligands for Natural Killer cells, thus alerting the immune system to the presence of invading pathogens. However, some MHC class I molecules, most notably HLA-B27, can be strongly associated with autoimmune diseases. In addition, the MHC class I pathway is a target for numerous viral evasion strategies Understanding not only the antigen presenting functions, but also the biosynthesis and the degradation pathways of MHC class I molecules has therefore 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 as well as complementary 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.