The mitochondrion is the unquestionable cellular compartment that actively preserves most of the cell functions, such as lipid metabolism, ion homeostasis, energy and ROS production, steroid biosynthesis, and control of apoptotic signaling. Thus, this cell organelle depicts a major drop-in centre for regulatory processes within a cell irrespective of the organ or tissue. However, brain tissue is unique in spite of everything due to its extremely high energy demand and sensitivity to oxidative stress. This makes brain cells, in particular neurons, considerably vulnerable against toxins and challenges that attack the mitochondrial structural organization and energetic performance. Estrogens are known to regulate a multitude of cellular functions in neural cells under physiological conditions but also play a protective role under neuropathological circumstances. In recent years, it became evident that estrogens affect distinct cellular processes by interfering with the bioenergetic mitochondrial compartment. According to the general view, estrogens indirectly regulate the mitochondrion through the control of genomic transcription of mitochondrial-located proteins and modulation of cytoplasmic signaling cascades that act upon mitochondrial physiology. More recent but still arguable data suggest that estrogens might directly signal to the mitochondrion either through classical steroid receptors or novel types of receptors/proteins associated with the mitochondrial compartment. This would allow estrogens to more rapidly modulate the function of a mitochondrion than hitherto discussed. Assuming that this novel perception of steroid action is correct, estrogen might influence the energetic control centre through long-lasting nuclear-associated processes and rapid mitochondria-intrinsic temporary mechanisms. In this article, we would like to particularly accentuate the novel conceptual approach of this duality comprising that estrogens govern the mitochondrial structural integrity and functional capacity by different cellular signaling routes. This article is part of a Special Issue entitled 'Neurosteroids'.