A growing body of evidence highlights the importance of microglia, the resident immune cells of the CNS, and their pro-inflammatory activation in the onset of many neurological diseases. Microglial proliferation, differentiation, and survival are highly dependent on the CSF-1 signaling pathway, which can be pharmacologically modulated by inhibiting its receptor, CSF-1R. Pharmacological inhibition of CSF-1R leads to an almost complete microglial depletion whereas treatment arrest allows for subsequent repopulation. Microglial depletion has shown promising results in many animal models of neurodegenerative diseases (Alzheimer's disease (AD), Parkinson's disease, or multiple sclerosis) where transitory microglial depletion reduced neuroinflammation and improved behavioral test results. In this review, we will focus on the comparison of three different pharmacological CSF-1R inhibitors (PLX3397, PLX5622, and GW2580) regarding microglial depletion. We will also highlight the promising results obtained by microglial depletion strategies in adult models of neurological disorders and argue they could also prove promising in neurodevelopmental diseases associated with microglial activation and neuroinflammation. Finally, we will discuss the lack of knowledge about the effects of these strategies on neurons, astrocytes, and oligodendrocytes in adults and during neurodevelopment.