PU.1 is an E26 transformation-specific family transcription factor that is required for development of the immune system. PU.1 functions at both early and late stages of lymphoid and myeloid differentiation. At least 110 direct target genes of PU.1 have been identified since its discovery in 1988. We used the published literature to determine if aspects of PU.1 function can be inferred from the identity of target genes that are directly activated. This analysis revealed that 61% of described PU.1 target genes encode extracellular proteins or transmembrane proteins, most of which are involved in cellular communication. The genes activated by PU.1 can be grouped into pathways based on function. Specific examples of cellular communication pathways regulated by PU.1 include (1) antibodies and antibody receptors, (2) cytokines and cytokine receptors regulating leukocyte growth and development, and (3) cytokines and cytokine receptors regulating inflammation. As a consequence of mutation or repression of the gene encoding PU.1, hematopoietic progenitors may be generated but there is a "failure to thrive" because they cannot interact with their environment. The loss of cellular communication caused by reduced PU.1 levels can lead to leukemia. In summary, PU.1 is a critical regulator of cellular communication in the immune system.