The outstanding problems facing immunology are whole system issues: curing allergic and autoimmune disease and developing vaccines to stimulate stronger immune responses against pathogenic organisms and cancer. We hope that the human genome sequence will reveal the molecular checks and balances that ensure both an effective immunogenic response against pathogenic microorganisms and a suitably tolerogenic response to self antigens and innocuous environmental antigens. Three synergistic approaches-sequence homology searches, messenger RNA expression profiling on microarrays, and mutagenesis in mice-provide the best opportunities to reveal, in the genome sequence, key proteins and pathways for targeting by new immunomodulatory treatments.