Inflammatory processes have a fundamental role in the pathophysiology of stroke. A key initial event is the rapid activation of resident immune cells, primarily microglia. This cell population is an important target for new therapeutic approaches to limit stroke damage. Activation of microglia is normally held in check by strictly controlled mechanisms involving neuronal-glial communication. Ischemic stroke is a powerful stimulus that disables the endogenous inhibitory signaling and triggers microglial activation. Once activated, microglia exhibit a spectrum of phenotypes, release both pro-and anti-inflammatory mediators, and function to either exacerbate ischemic injury or help repair depending on different molecular signals the microglial receptors receive. Various ligands and receptors have been identified for microglial activation. Experimental tools to detect these inflammatory signals are being increasingly developed in an effort to define the functional roles of microglia. Fine-tuning immunomodulatory interventions based on the heterogeneous profiles of microglia are urgently needed for ischemic stroke.