Microglia (MG), the primary macrophage of the central nervous system, are highly specialized to meet the brains' functional demands. In health, MG maintain homeostasis by continuously surveying the brain parenchyma, detecting immune signaling, sensing ATP, influencing synapses, and responding to injury. Upon inflammation or injury, MG can become dysregulated and contribute to disease pathology. While the underlying mechanisms of MG dysregulation in many diseases are incompletely understood, even those we understand are difficult to treat due to limited ability to directly target MG. What if instead of trying to target each genetic component dysregulated in microglia, we could instead replace host microglia with healthy donor cells? This idea, termed microglia replacement therapy, involves depleting and subsequently replacing endogenous microglia with surrogate cells.In this dissertation, I discuss the pivotal roles microglia play in neurological diseases and encouraging data from new transplantation strategies that support the idea that targeting microglia is a promising strategy for cell-based interventions for neurological disorders. Next, I discuss the work I completed in my Ph.D. to develop more efficient and safer methods of microglia replacement therapies. With these projects, I addressed several roadblocks that previously limited the feasibility of microglia-based immunotherapies therapies. I created a high temporal resolution dataset detailing how microglia identity is programmed by the brain, I identified several targets involved in programming microglial identity that warrant further study, created tools to replace microglia in safe non-toxic manners, and I developed methods to deliver donor cells both intracranially and peripherally in a tissue-specific manner. In the final chapter, I discuss how ongoing and future studies might expand on these data. I hope that the findings discovered in my Ph.D. contribute to the expanding toolkit responsible for bringing microglia replacement therapies - and their transformative potential - closer to becoming a reality.