My laboratory carries out research to elucidate novel molecular mechanisms that regulate the human immune system, especially lymphocytes, and how their derangements cause susceptibility to viral and other infections. We do this by using state-of-the-art genomic approaches to study patients who have rare and poorly characterized inherited immunodeficiencies, By carefully investigating these “experiments of nature” we can draw inferences about molecular functions based on patient phenotype. Because cell-mediated immunity is crucial in protection against viral infections, we have observed that these patients usually have partial T cell or combined immunodeficiencies, which are often accompanied by autoimmunity or lymphoproliferation. Through a broad program that integrates the patients’ clinical evaluations, assessments of their leukocyte function, genetic and biochemical analyses, especially using new technologies such as whole exome analysis and advanced microscopy, we gain profound insights into the molecular and cellular basis of immunity against viruses. Although in some instances parallel insights can be gained from experimental animals, in other instances, we learned unique lessons from investigating the human disease to define new clinical entities and their molecular pathogenesis. By utilizing the latest molecular, genomic, and cellular technologies to elucidate the fundamental mechanisms that normally regulate human lymphocytes for host defense, we also aim to improve diagnosis and treatment for these and related immunological conditions.