Macrophages (MFs) were originally identified by the Nobel laureate Ilya Metchnikoff as cells specialized in the killing of micro-organisms. However, genetic profiling of MFs from various tissues has demonstrated the astonishing diversity of MFs, suggesting that each MF is profoundly adapted to its tissue of residence and performs unique local functions. However, what these unique functions might be is only poorly understood. We hypothesize that the primary day-to-day function of tissue-resident MFs is not host defense but rather to fulfill crucial “accessory functions” for their tissue of residence. These accessory functions are functions that over the course of evolution have been “outsourced” by the parenchymal cells to MFs, but which remain nonetheless vital for the well-functioning of each of these organs. In this project we propose to use a systems immunology approach to unravel the accessory functions of the most abundant MF in the body: the liverresident Kupffer Cell (KC). Therefore, we aim at a tight integration between genetic and computational tools, making efficient use of large scale screening methodologies such as transcriptomics and multi-color flow cytometry. The ambition of this project is to disentangle the molecular mechanisms that govern the accessory functions of KCs. This should unravel the role of these cells that were identified more than a century ago, but also pave the way for the development of future therapeutic interventions for liver diseases.