Ischemic stroke is caused by abrupt disruption of brain blood supply, which triggers neural cell death within minutes. Acute brain tissue damage causes inflammation and triggers immune responses. Currently there are no treatments to successfully modulate these responses to induce brain protection after stroke. Understanding crucial cellular and molecular determinants of the immune responses after stroke is imperative to achieve effective solutions for brain protection and restoration of homeostasis. Danger signals or damage-associated molecular patterns, including nuclear proteins, nucleic acids, heat-shock proteins, amongst others, are released from the injured cells and trigger immune responses by activating pattern recognition receptors (PRRs). Microglial cells are equipped with membrane PRRs, can sense danger signals in the environment and induce inflammation. In addition, intracellular PRRs recognize cytosolic nucleic acids resulting from cellular stress and damage and activate the receptor stimulator of interferon inducing type I interferon (IFN) pathway. This pathway must be precisely regulated given that gain of function and subsequent chronic IFN type I overproduction is involved in the pathogenesis of autoimmune diseases. In old mice, microglia accumulate lipids and show stronger type I IFN responses after stroke, which causes more neurological impairment in aged than young mice. Designing strategies to restore the perturbed function of microglial cells of old mice is an attractive goal to improve stroke outcome in the elderly. Injury-activated microglia release cytokines attracting leukocytes to the lesion. Several lines of evidence support pro-reparative roles of some infiltrating monocytes and lymphocytes by paving the way to lesion resolution and repair.