Abstract: Colony stimulating factor 1 receptor (CSF1R) is a tyrosine kinase receptor primarily expressed on microglia and a small subpopulation of neurons in the central nervous system (CNS), which directly controls the homeostasis, activation, and proliferation of microglia. Its ligands include CSF1 and interleukin-34 (IL-34), which bind to the same region of CSF1R. The two ligands have overlapping functions, however, they also have some differences in signal transduction and induce different transcription profiles. CSF1 and IL-34 are generally expressed by neurons in the CNS, but CSF1 is also expressed by astrocytes. The colony stimulating factors were first characterized by their ability to trigger the differentiation of bone marrow precursor cells into mature myeloid cells but were later found to also act on mature myeloid cells including microglia. In the homeostatic brain, a baseline level of CSF1 helps to maintain microglial roles of synaptic pruning, release of neurotrophic factors, and promotion of brain connectivity. However, over the past decade or so, chronic activation of microglia has been implicated in exacerbating neurodegenerative disorders, including Alzheimer’s disease (AD), Parkinson’s disease, multiple sclerosis (MS), and amyotrophic lateral sclerosis (ALS) (Xu et al., 2021). Yet there have also been studies in contradiction, which showed that in other circumstances, activated microglia were therapeutic and might mitigate neurodegeneration. So, is CSF1 the friend or foe of neurons?