Each type of cell in the immune system performs critical functions to protect the body and maintain health. In order to fulfil these roles some immune cells rely on unique processes, including antigen receptor loci recombination, clonal expansion or the contortion of their nuclei. In turn, each of these processes relies on, or poses unique challenges to, a genome organized in three dimensions. Here, we explore the current understanding of the importance of 3D genome organization in the function and development of a healthy immune system.