The advance of systems biology approaches now means that much of the immune response to pathogens and vaccines can be assessed. Modern immunologists have at their disposal an arsenal of high-throughput technologies and tools that generate data relating the quantities of genes, metabolites and proteins within immune cells. The challenge posed is how to interpret this abundance of data to accurately understand and predict the immune response. Systems immunology is the discipline that uses computational and mathematical approaches to integrate these measurements and explain the nonintuitive interactions between biological components. In this chapter we will provide an overview of this interdisciplinary approach, its challenges, and highlight some of the applications of systems biology to assess the complexity of our immune system.