Macrophages isolated from different tissues have distinct niche roles that maintain tissue homeostasis, as well as providing surveillance for tissue injury or infection. The potential to model tissue residency, disease phenotypes and activation status of human macrophages using pluripotent stem cells is both exciting and a growing area of interest. Benchmarking pluripotent stem cell-derived macrophages to primary macrophages has previously been limited by the availability of data on a compatible platform and the number of comparisons carried out. By assembling an integrated transcriptome atlas of human myeloid biology representing ∼1000 samples, we address the question of how well laboratory models, including pluripotent-derived cells, represent macrophage biology, and particularly whether these can model resident tissue macrophage specialisation. Through our analysis, we identified two broad classes of tissue-resident macrophages with lung, gut and tumour-associated macrophages most similar to monocytes. Microglia, Kupffer cells and synovial macrophages shared similar profiles with each other, and with cultured macrophages. In comparison, pluripotent stem cell-derived macrophages were found to sit away from in vivo cell types despite sharing some features with tissue-resident macrophages. Gene-set enrichment analysis of the genes that most correlated with in vitro-derived macrophages moving away from the tissue-resident populations revealed that the most significant pathways in these cells involved collagen synthesis and production Moreover, by single cell projection of human fetal yolk sac cell clusters onto the atlas, we further found that pluripotent stem cell-derived macrophages to not be reminiscent of fetal-derived cells. Overall, our analyses highlight that there is room for improvement in the development of in vitro model systems that attempt to mimic in vivo counterparts.