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Microglia are the resident immune cells of the brain. As such, their activation is associated with a range of conditions in the healthy and inflamed CNS. In the healthy brain, microglia maintain homeostasis by continuously sampling their environment [1]. When CNS infection and/or inflammation occurs, microglia respond appropriately by changing their activation state. Recent studies illustrate that microglial activation is not an “all or nothing” event. Instead, like peripheral macrophages, microglia exhibit a range of activation states associated with pathogen defense, wound healing, and tissue repair functions (Fig. 1.1) [2, 3]. In addition, although microglia can change their morphology in response to specific stimuli, morphology is now well demonstrated to be a poor discriminator between different types of activation (Fig. 1.1) [2–4].