With the development of monoclonal antibody and flow cytometry technologies, the identification of cells expressing certain markers (phenotypes) and the association of phenotypes with differentiation state and function have become feasible. Clinicians can more clearly define defects and better understand the cellular responses in immunodeficiency diseases and determine the effects of therapy on these patients. This article addresses aspects of immunophenotyping in primary (genetic or with unknown cause) and secondary (acquired or with a known cause) immunodeficiencies with regard to diagnosis, characterization, and therapy.