The multistep process that culminates in major histocompatibility complex (MHC) class I presentation of foreign of self-peptides begins in the last phases of protein catabolism. Although the individual roles of many key molecules-such as proteasomes, the transporter associated with antigen processing, and various endoplasmic reticulum chaperones-have recently been elucidated, there still remain many questions regarding processing of proteins into MHC class I bound peptides. This review summarizes the recent developments in antigen processing for MHC class I molecules, with a focus on how proteins are believed to be sampled and selected for degradation.