Prothymosin α (ProTα) possesses multiple functions for cell robustness. This protein functions intracellularly to stimulate cell proliferation and differentiation through epigenetic or genomic mechanisms. ProTα also regulates the cell defensive mechanisms through an interaction with the Nrf2-Keap1 system. Under the apoptotic conditions, it inhibits apoptosome formation by binding to Apaf-1. Regarding extracellular functions, ProTα is extracellularly released from the nucleus upon necrosis-inducing ischemia stress in a manner of nonclassical release, and thereby inhibits necrosis. However, under the condition of apoptosis, the C-terminus of ProTα is cleaved off and loses binding activity to cargo protein S100A13 for nonclassical release. However, cleaved ProTα is retained in the cytosol and inhibits apoptosome formation. ProTα was recently reported to cause immunological actions through the Toll-like receptor 4. However, the authors also suggest the possible existence of additional receptors for robust cell activities against ischemia stress.