Recent studies have revealed extensive heterogeneity between functionally distinct macrophage subsets, including microglia. Transcription factors of the CCAAT-enhancer binding protein (C/EBP) family are key regulators of the formation and function of myeloid cells. Various C/EBP isoforms and a plethora of post-translational modifications have been found to alter myeloid cell type specification and gene expression patterns, suggesting a role of C/EBP also in neuroinflammation and neurodegeneration. We will elucidate the role of C/EBP in microglia using a two-tiered molecular genetic- and proteomics approach, in combination with functional analysis. On one hand, various C/EBP knockin mouse mutant strains are amenable to examination during health and disease. Histo-morphological analysis, in combination with transcriptomics will help to describe microglial C/EBP regulation. On the other hand, state-of-the-art mass-spectrometry, protein engineering and genome editing will be employed as an integrated approach to unravel the C/EBP dependent proteome/interactome. The combined approaches in a concerted fashion will help to decipher C/EBP mediated neuroimmune functions during healthy and inflammatory conditions.