Microglial activation is an early and common feature of almost all neuropathologies, including multiple sclerosis, Alzheimer's disease and mechanical injury. To better understand the relative contributions microglia make toward neurodegeneration and neuroprotection, we used TOGA^® to identify molecules expressed by microglia and regulated by inflammatory signals. Triggering receptor expressed on myeloid cells‐2 (TREM‐2) was among the mRNAs identified as being expressed by unactivated microglia, but down‐regulated by lipopolysaccharide/interferon γ. In the healthy CNS, not all microglia expressed TREM‐2. Microglial expression of TREM‐2 varied not only between brain regions but also within each brain region. Brain regions with an incomplete blood–brain barrier had the lowest percentages of TREM‐2‐ expressing microglia, whereas the lateral entorhinal and cingulate cortex had the highest percentages. A novel form of TREM‐2b that lacked a transmembrane domain was detected, perhaps indicating a soluble form of the protein. Taken together, these data suggest that (1) subsets of microglia are specialized to respond to defined extracellular signals; and (2) regional variations in TREM‐2 expression may contribute to the varying sensitivities of different brain regions to similar pathological signals.