Macrophages were identified by the Nobel laureate Ilya Metchnikoff (1845–916). Genetic profiling of macrophages from various tissues has demonstrated the astonishing diversity of these cells, suggesting that each macrophage is profoundly adapted to its tissue of residence. Using selfgenerated knock-in mice that allow the specific depletion of liver macrophages, we found that monocytes colonize the liver niche in a single wave upon macrophage depletion and rapidly differentiate into liver macrophages that are transcriptionally identical to their depleted counterparts. We now aim to unravel the regulatory dynamics underlying liver macrophage differentiation. There must be factors inducing the expression of the liver-specific gene signature. Such factors are called transcription factors. By combining expertise in computational modelling (Saeys group) and self-generated experimental mouse models (Guilliams group) we will design new data mining algorithms that will allow to model liver macrophage differentiation from highthroughput single-cell datasets. Importantly, our novel mouse models will allow the in vivo validation of these in silico predictions. We aim to unravel which external factors imprint the livermacrophage identity, through which transcription factors they operate and which genes are directly controlled by these transcription factors. This should at last unravel the factors that drive the development of these cells that were identified more than a century ago.