Humanin (HN) is a newly discovered 24-amino acid peptide, which may suppress neuronal cell death. HN cDNA includes an open reading frame (HN-ORF) of 75 bases located 950 bases downstream of the 5' end of the HN cDNA. It has been demonstrated that HN cDNA is 99% identical to the mitochondrial DNA (mtDNA) sequence. HN homologs have been identified as expressed sequence tags (ESTs) in both rats and nematodes. Certain regions that are homologous to the HN cDNA exist on human chromosomes. HN forms homodimers and multimers and this action seems to be essential for peptide function. HN acts as a ligand for formyl peptide receptor-like 1 (FPRL1) and 2 (FPRL2). It has been demonstrated that HN plays a protective role through its antiapoptotic activity that interferes with Bax activation, which suppresses Bax-dependent apoptosis. HN has also been shown to suppress the c-Jun N-terminal kinase (JNK) and ASK/JNK-mediated neuronal cell death. Several studies have also confirmed that HN could be important in the prevention of angiopathy-associated Alzheimer's disease dementia, diseases related to mitochondrial dysfunction (MELAS), and other types of β-amyloid accumulation-associated neurodegeneration. Avery recent study demonstrated a pluripotent cytoprotective effect and mechanisms of HNs in cells not from the CNS, such as germ cells or pancreatic β-cells, and the potent physiological consequences that result from HN interaction with IGFBP3 and STAT3. In vivo studies suggest that HN may also protect against cognitive impairment due to ischemia/reperfusion injury.