Immunity is governed by fundamental genetic processes. These processes shape the nature of immune cells and set the rules that dictate the myriad complex cellular interactions that power immune systems. Everything from the generation of T cell receptors and antibodies, control of epitope presentation, and recognition of pathogens by the immunoediting of cancer cells is, in large part, made possible by core genetic mechanisms and the cellular machinery that they encode. In the last decade, next-generation sequencing has been used to dissect the complexities of cancer immunity with potent effect. Sequencing of exomes and genomes has begun to reveal how the immune system recognizes "foreign" entities and distinguishes self from non-self, especially in the setting of cancer. High-throughput analyses of transcriptomes have revealed deep insights into how the tumor microenvironment affects immunotherapy efficacy. In this Review, we discuss how high-throughput sequencing has added to our understanding of how immune systems interact with cancer cells and how cancer immunotherapies work.