The treatment of acute ischemic stroke is still an unresolved clinical problem since the only approved therapeutic intervention relies on early blood flow restoration through pharmacological thrombolysis, mechanical thrombus removal, or a combination of both strategies. Due to their numerous complications and to the narrow time-window for the intervention, only a minority of stroke patients can actually benefit from revascularization procedures, highlighting the urgent need of identifying novel strategies to prevent the progression of an irreversible damage in the ischemic penumbra. During the past three decades, the attempts to target the pathways implicated in the ischemic cascade (e.g., excitotoxicity, calcium channels overactivation, reactive oxygen species (ROS) production) have failed in the clinical setting. Based on a better understanding of the pathobiological mechanisms and on a critical reappraisal of most failed trials, numerous findings from animal studies have demonstrated that targeting the immune system may represent a promising approach to achieve neuroprotection in stroke. In particular, given the dualistic role of distinct components of both the innate and adaptive arms of the immune system, a strategic intervention should be aimed at establishing the right equilibrium between inflammatory and reparative mechanisms, taking into consideration their spatio-temporal recruitment after the ischemic insult. Thus, the application of immunomodulatory drugs and their ability to ameliorate outcomes deserve validation in patients with acute ischemic stroke.