Macrophages are essential innate immune cells that maintain tissue homeostasis and defend the host against pathogens. During my DPhil, I investigated the functions and transcriptional regulation of macrophages under different physiological and pathological contexts.In the first part of my research, I explored several previously described in vitro models of tumor-associated macrophages (TAMs) that mimic distinct features of the tumor microenvironment, including exposure to soluble factors secreted by cancer cells, mixed immune-stimulatory and -suppressive cytokine signals, and metabolites characteristic of highly glycolytic tumors.Subsequently, I focused on developing a new method for pooled CRISPR screening in primary human macrophages. Using this approach, I systematically interrogated known human transcription factors in the context of M-CSF-mediated macrophage survival and identified ZNF207 as a novel negative regulator. Functional characterization revealed that ZNF207 plays a pleiotropic role in macrophage survival, polarization, and efferocytosis, with important implications for tissue homeostasis and the resolution of inflammation.Following submission of this thesis, I intend to further elucidate the mechanisms by which ZNF207 regulates macrophage survival, differentiation, and function.