OBJECTIVE: To propose a new classification for the primary immunodeficiency disorders and to review potential therapeutic applications of biologic response modifiers in these disorders. DATA SOURCE: Relevant articles were identified through a search of MEDLINE using the following indexing terms: primary immunodeficiencies (and subclassifications), and human immunomodulators (and subclassifications). STUDY SELECTION: Articles were critically reviewed and included if relevant. DATA SYNTHESIS: The primary immunodeficiency disorders are classified according to functional abnormalities, specifically, abnormalities in early cellular maturation, differentiation, regulatory cell function, enzymatic function, and cytokine responses. Such a classification clarifies the potential role of biologic response modifiers in primary immunodeficiency disorders. Intravenous gammaglobulin and histamine-2 (H2)-receptor blockers modify regulatory cell function; retinoids modify abnormal cellular differentiation, gene transfer and enzyme replacement can be applied in disorders characterized by specific functional gene abnormalities; and interferons modify abnormal cytokine responses. Interleukin-2, thymic hormones, transfer factor, and levamisole appear to affect multiple functional defects. CONCLUSIONS: Biologic response modifiers are currently important ancillary tools in the treatment of immunodeficiency disorders, and their therapeutic role will become even more important in the future. Multi-center cooperative trials of new and existing agents are needed to fully define their roles and efficacy in the treatment of these disorders.