Interleukin (IL)-10 is an essential anti-inflammatory cytokine that plays important roles as a negative regulator of immune responses to microbial antigens. Loss of IL-10 results in the spontaneous development of inflammatory bowel disease as a consequence of an excessive immune response to the gut microbiota. IL-10 also functions to prevent excessive inflammation during the course of infection. IL-10 can be produced in response to pro-inflammatory signals by virtually all immune cells, including T cells, B cells, macrophages, and dendritic cells. Given its function in maintaining the delicate balance between effective immunity and tissue protection, it is evident that IL-10 expression is highly dynamic and needs to be tightly regulated. The transcriptional regulation of IL-10 production in myeloid cells and T cells is the topic of this review. Drivers of IL-10 expression as well as their downstream signaling pathways and transcription factors will be discussed. We will examine in more detail how various signals in CD4⁺ T cells converge on common transcriptional circuits, which fine-tune IL-10 expression in a context-dependent manner.