The immune system of higher organisms has the unique capability of mounting a specific and adaptive response against invading pathogens. Specific in the sense that immune cells recognize molecular features from foreign pathogens, and adaptive in the sense that upon reencounter of the foreign pathogen the immune system respond faster and more efficiently, which is the basic principle used in vaccination. In addition, the immune system has evolved the innate capability of recognizing common, slow mutating features on pathogens by using several different pattern recognition receptors. These defense mechanisms are important, but just like any other organisms pathogens also mutate to adapt to selection pressures thereby escaping immune surveillance. Likewise, the immune system of higher organisms is not a static system, but rather a dynamic ever-changing defense system continuously evolving over millions of years to constantly battle pathogens trying to overcome immune defense barriers and take over the host protein translation machinery. Furthermore, the immune system needs to be in balance with its host, but sometimes the line between functional immunity and auto-reactivity becomes hard to draw. Importantly, it is now a firmly established concept that the immune system eradicates host cells undergoing malignant transformation to prevent tumor formation. With these functions in mind, it is reasonable to claim the adaptive immune system as highly essential in the protection of pathogenic infections and malignant cells. The adaptive immune system contains a variety of T cells; two major groups are the CD4+ T cells that interact with MHC class II (MHC-II) cell surface receptors, and CD8+ T cells, also termed cytotoxic T cells (CTLs) that interact with MHC class I (MHC-I) cell surface receptors. The CTLs kill malignant host cells or host cells infected with foreign pathogens. This chapter focuses on the immunology concerning CTLs and MHC-I. Specifically, we focus on the multi-step, intracellular maturation of MHC-I.