Cerebral ischemia due to stroke or cardiac arrest greatly affects daily functioning and the quality of life of patients and has a high socioeconomic impact due to the surge in their prevalence. Advances in the identification of an effective pharmacotherapy to promote neuroprotection and recovery after a cerebral ischemic insult are, however, limited. The serotonin 1A (5-HT1A) receptor has been implicated in the regulation of several brain functions, including mood, emotions, memory, and neuroplasticity, all of which are deleteriously affected by cerebral ischemia. This review focuses on the specific roles and mechanisms of 5-HT1A receptors in neuroprotection in experimental models of cerebral ischemia. We present experimental evidence that 5-HT1A receptor agonists can prevent neuronal damage and promote functional recovery induced by focal and transient global ischemia in rodents. However, indiscriminate activation of pre-and postsynaptic by non-biased 5-HT1A receptor agonists may be a limiting factor in the anti-ischemic clinical efficacy of these compounds since 5-HT1A receptors in different brain regions can mediate diverging or even contradictory responses. Current insights are presented into the 'biased' 5-HT1A post-synaptic heteroreceptor agonist NLX-101 (also known as F15599), a compound that preferentially and potently stimulates postsynaptic cortical pyramidal neurons without inhibiting firing of serotoninergic neurons, as a potential strategy providing neuroprotection in cerebral ischemic conditions.