MHC class I (MHC-I) molecules undergo an intricate folding process in order to pick up antigenic peptide to present to the immune system. In recent years, the discovery of a new peptide editor for MHC-I has added an extra level of complexity in our understanding of how peptide presentation is regulated. On top of this, the incredible diversity in MHC-I molecules leads to significant variation in the interaction between MHC-I and components of the antigen processing and presentation pathway. Here, we review our current understanding regarding how polymorphisms in human leukocyte antigen class I molecules influence their interactions with key components of the antigen processing and presentation pathway. A deeper understanding of this may offer new insights regarding how apparently subtle variation in MHC-I can have a significant impact on susceptibility to disease.