New scientific technologies applied to patients with rare diseases are facilitating discoveries about how the human immune system is regulated at the molecular level. Studies of patients with autoimmune lymphoproliferative syndrome (ALPS) or caspase-8 deficiency state (CEDS) demonstrated the ability of gene expression microarray analyses and small interfering RNAs (siRNA) to establish the physiologically important roles of NRAS, caspase-10, and caspase-8 for normal lymphocyte apoptosis and activation. The advent of genomics technologies such as next generation sequencing will complement these and more traditional approaches. These advances are anticipated to accelerate the pace of new discoveries in patients with immunological disorders.