The basic helix-loop-helix transcription factor (TF) Bhlhe40 is emerging as a key regulator of immunity during infection, autoimmunity, and inflammatory conditions. We describe the roles of Bhlhe40 in the circulating and tissue-resident arms of the immune system, with emphasis on recent work on the regulation of cytokine production and proliferation. We explore the mechanisms behind these functions in mouse models and human cells, including interactions with other TFs, and propose that Bhlhe40 is a central mediator of both inflammation and pathogen control, as well as a crucial regulator of a growing number of tissue-resident leukocyte populations. Finally, we suggest areas for further study that may advance our understanding of immunity and disease. Bhlhe40 is a key regulator of cytokine production by human and mouse T cells.Bhlhe40 can drive inflammation and enables typical immune responses in autoimmunity, transplantation, cancer, and infection.Bhlhe40 is a tissue-specific regulator of murine tissue-resident macrophage proliferation.Bhlhe40 and Bhlhe41 are required by mouse B1a cells for normal proliferation, survival, and BCR repertoire.Bhlhe40 is essential for mitochondrial metabolism in mouse tissue-resident memory CD8+ T cells and tumor-infiltrating lymphocytes.Bhlhe40 contributes to controlling the balance between inflammation and disease tolerance, and promotes highly inflammatory responses.