Mitochondria are power organelles generating biochemical energy, ATP, in the cell. Mitochondria play a variety of roles, including integrating extracellular signals and executing critical intracellular events, such as neuronal cell survival and death. Increasing evidence suggests that a cross-talk mechanism between mitochondria and the nucleus is closely related to neuronal function and activity. Nuclear receptors (estrogen receptors, thyroid (T3) hormone receptor, peroxisome proliferators-activated receptor gamma2) and transcription factors (cAMP response binding protein, p53) have been found to target mitochondria and exert prosurvival and prodeath pathways. In this context, the regulation of mitochondrial function via the translocation of nuclear receptors and transcription factors may underlie some of the mechanisms involved in neuronal survival and death. Understanding the function of nuclear receptors and transcription factors in the mitochondria may provide important pharmacological utility in the treatment of neurodegenerative conditions. Thus, the modulation of signaling pathways via mitochondria-targeting nuclear receptors and transcription factors is rapidly emerging as a novel therapeutic target.