When endogenous ouabain was first isolated from human plasma in 1991, many expressed doubts that such a compound could be endogenous to humans because of its unusual structure, its unknown synthesis, and its unidentified site of origin. Furthermore, the relevance of human ouabain was questioned because of its apparently low (< or =nmol/L) circulating concentration. Since then, much progress has been made on the origin and synthesis of endogenous ouabain, but perhaps the most significant finding is that nanomolar concentrations of ouabain can induce numerous signal transduction events in both primary and immortalized cultures of cells. Here we analyze the effects of low ouabain-induced signals including cell proliferation, calcium mobilization, cell cytotoxicity, apoptosis, mitogen-activated protein kinase (MAPK) activation and other signaling pathways. Furthermore, we consider how these low dose ouabain-induced events might enable a putative role for human endogenous ouabain to be assigned.