Over millions of years of coevolution with their hosts, viruses have developed highly effective strategies to elude the host immune system. The degradation of major histocompatibility complex (MHC) class I heavy chains by human cytomegalovirus (HCMV) is an example of this. Two HCMV proteins, US2 and US11, target newly synthesized MHC class I heavy chains for destruction via a pathway that involves ubiquitin-dependent retrograde transport, or "dislocation", of the heavy chains from the ER to the cytosol, where the proteins are degraded by proteasomes. In this review, US2- and US11-mediated degradation of MHC class I heavy chains is discussed in relation to data concerning the degradation of other ER luminal proteins. A new, unified model for translocon-facilitated dislocation and degradation of MHC class I heavy chains is presented.