Microglia cells exhibit two forms of motility, constant movement of filopodia probing surrounding brain tissue, and outgrowth of larger processes in response to nearby damage. The mechanisms and functions of filopodia sensing and process outgrowth are not well characterized but are likely critical for normal immune function in the brain. Using two photon laser scanning microscopy we investigated microglia process outgrowth in response to damage, and explored the relationship between process outgrowth and filopodia movement. Further, we examined the roles of Cl⁻ or K⁺ channel activation, as well as actin polymerization in these two distinct processes, because mechanistic understanding could provide a strategy to modulate microglia function. We found that volume sensitive Cl⁻ channel blockers (NPPB, tamoxifen, DIDS) prevented the rapid process outgrowth of microglia observed in response to damage. In contrast, filopodia extension during sensing was resistant to Cl⁻ channel inhibitors, indicating that these motile processes have different cellular mechanisms. However, both filopodia sensing and rapid process outgrowth were blocked by inhibition of actin polymerization. Following lesion formation under control conditions, rapidly outgrowing processes contacted the damaged area and this was associated with a 37% decrease in lesion volume. Inhibition of process outgrowth by Cl⁻ channel block, prevention of actin polymerization, or by selectively ablating microglia all allowed lesion volume to increase and spread into the surrounding tissue. Therefore, process outgrowth in response to focal brain damage is beneficial by preventing lesion expansion and suggests microglia represent a front line defence against damage in the brain. © 2009 Wiley‐Liss, Inc.