17β-estradiol (E2) plays a crucial role in the maintenance of body homeostasis including the balance between cell survival and apoptosis. Intriguingly, estrogen receptor subtypes (i.e., ERα and ERβ) trigger opposite pathways which drive E2 target cells to proliferation (via ERα) or apoptosis (via ERβ). Recently, we identified neuroglobin (NGB) as an E2 inducible heme-protein involved in hormone regulation of cell proliferation and apoptosis in neuronal and non-neuronal cell lines. In particular, E2 increases NGB protein level mainly in the mitochondria preventing the release of cytochrome c after an oxidative stress injury. Here, the mechanisms underlying E2-induced NGB up-regulation, the involvement of signal transduction pathways and of specific ER subtypes will be discussed in order to propose a possible new E2-dependent scenario at the root of cell survival and cell death balance.