Many prokaryotic and eukaryotic parasites multiply in specialized subcellular niches in the host cell. The invading microbes hijack key cellular functions to establish the intracellular niches but, unlike viruses, do not need the protein synthesis machinery of host cells to replicate. Circulating CD8+ T cells provide protective immunity by recognizing pathogen-derived peptide major histocompatibility complex class I molecules (pMHC I) expressed by infected cells. Here, we review studies on the complex and varied pathways that produce the appropriate pMHC I as ligands for the CD8 + T cells. We also discuss possible explanations for the curious observations that CD8+ T cells are specific for fewer pMHC I ligands in parasite infections compared to the diversity of pMHC I ligands in viral infections.