Microglia are the primary innate immune cells in the CNS. In the healthy brain, they exhibit a unique molecular homeostatic ‘signature’, consisting of a specific transcriptional profile and surface protein expression pattern, which differs from that of tissue macrophages. In recent years, there have been a number of important advances in our understanding of the molecular signatures of homeostatic microglia and disease-associated microglia that have provided insight into how these cells are regulated in health and disease and how they contribute to the maintenance of the neural environment.