Macrophages are specialised cell types resident in most tissues of the body, and with diverse roles in homeostasis, host defence and tissue repair. While transcription factors such as PU1.1 and other master regulators of human macrophage differentiation are well understood, the chromatin changes that these orchestrate to direct macrophage specialisation are superficially mapped. To increase molecular resolution of developing macrophage networks, we undertook multiomics analysis that includes CAGE mapping of enhancers and promoters, long-read transcript sequencing to identify the isoforms that direct macrophage gene expression networks, and proteomics to identify the specific protein isoforms that are generated through macrophage development. Micro-C and RADCL-seq further map the chromatin interactions that coincide with these transcriptional and phenotypic changes. We identified the Neuregulin 1 locus as a region of particular interest, with the discovery of a myeloid class of NRG1-VII, which is dynamically regulated in progenitors and macrophages. The combined dataset provides unprecedented resolution of the molecular networks that underpin human macrophage differentiation.