Acute systemic inflammatory reaction superimposed on chronic low-grade inflammation accompanies acute ischemic stroke. Elevated blood levels of systemic inflammatory markers such as IL-6 or C-reactive protein are associated with an unfavorable functional outcome and increased mortality after stroke. Animal studies have demonstrated a causal relationship between systemic inflammation and ischemic brain damage. The mechanisms linking systemic inflammation with poor outcome include increased neutrophil infiltration of cerebral cortex, disruption of the blood–brain barrier, impaired tissue reperfusion, increased platelet activation and microvascular coagulation and complement-dependent brain injury. Non-selective (e.g., by statins) or selective (e.g., by inhibition of IL-6) attenuation of systemic inflammation, enhancement of systemic anti-inflammatory response (e.g., by infusion of IL-1 receptor antagonist), prevention of infections that exacerbate systemic inflammation or inhibition of neuronal pathways triggering inflammatory reaction are potential therapeutic targets in stroke patients. This review discusses the relationship between systemic inflammation, cerebral ischemia and prognosis in the context of therapeutic strategies.