Hypusine, an unusual amino acid, is derived from the hydrolysis of eukaryotic initiation factor SA (eIF-5A), the only cellular protein known to contain hypusine residue. Hypusine residue is formed through a spermidine-dependent posttranslational modification of eIF-5A at a specific lysine residue. Each mature eIF-5A molecule contains only one hypusine. Hypusine formation on eIF-5A is essential for cell survival and proliferation. The biochemistry of hypusine formation has, been actively investigated in a number of leading laboratories during the past decade. The precise functional role of eIF-5A remains a mystery. This paper reviews recent progress in the study of the biochemistry of hypusine formation and offers speculation on the possible function of eIF-5A.