The field of immunology has a rich and diverse history, and the study of inborn errors of immunity (IEIs) represents both the "cake" and the "icing on top of the cake," as it has enabled significant advances in our understanding of the human immune system. This explosion of knowledge has been facilitated by a unique partnership, a triumvirate formed by the physician who gathers detailed immunological and clinical phenotypic information from, and shares results with, the patient; the laboratory scientist/immunologist who performs diagnostic testing, as well as advanced functional correlative studies; and the genomics scientist/genetic counselor, who conducts and interprets varied genetic analyses, all of which are essential for dissecting constitutional genetic disorders. Although the basic principles of clinical care have not changed in recent years, the practice of clinical immunology has changed to reflect the prodigious advances in diagnostics, genomics, and therapeutics. An "omic/tics"-centric approach to IEI reflects the tremendous strides made in the field in the new millennium with recognition of new disorders, characterization of the molecular underpinnings, and development and implementation of personalized treatment strategies. This review brings renewed attention to bear on the indispensable "trinity" of phenotypic, genomic, and immunological analyses in the diagnosis, management, and treatment of IEIs.