The immune system with its hallmark property of recognition and response is the central defence system of our body that confers protection upon us against infection and disease. Infectious agents include a wide range of organisms ranging from viruses, bacteria, protozoans, fungi, to various worms. The immune system comprises two principal components: the nonspecific innate immune system, which provides the initial resistance to infection, and the specific or the adaptive immune system, which develops slowly and provides specialised effectors against infections. The cellular and humoral components of the innate and adaptive immune system work in coordination to combat infection and disease. However, aberrations in the function of the immune system leads to disease, some of which are life threatening. It is, therefore, very important to understand the complex nature of any such aberration so that an effective therapy can be designed. Computational immunology holds great promise by designing databases of diseases and pathogens, modelling disease transmission and epidemiology, analysing information from the sequencing of organisms, understanding cell fates in T-cell and B-cell differentiation, understanding host–pathogen interaction dynamics, designing drugs and vaccines for life-threatening disorders, and designing an approach towards personalised medicine. In this chapter we discuss (i) a brief the overview of the immune system, (ii) computational immunology, (iii) the history of computational immunology, (iv) recent developments in computational immunology, and (v) the road ahead at this point. The complexity of the immune system and diseases and the approaches of computational immunology to solve such complexity and better our understanding of the biology of disease are discussed in detail in subsequent chapters.