Background Forkhead box O (FOXO) 3a transcription factors are regulators of cell-type specific apoptosis and cell cycle arrest but also control longevity and reactive oxygen species (ROS). Objective We discuss that a FOXO3a self-reactivating loop and novel functions of FOXO3a in controlling mitochondrial respiration of neuronal cells, which further supports the current view that FOXO3a transcription factors are information-integrating sentinels of cellular stress and critical modulators of cell homeostasis. Content In this article we will discuss the current knowledge on the involvement of FOXO3a transcription factors in the regulation of cellular homestasis with specific emphsis on mitochondrial integrity, morphology and activity. In neuronal tumor cells, FOXO3a triggers ROS-accumulation as a consequence of transient mitochondrial outer membrane permeabilization, which is essential for FOXO3a-induced apoptosis in these cells. Cellular ROS levels are affected by the FOXO3a-targets Bim, BclxL, and Survivin. All three proteins localize to mitochondria and affect mitochondrial membrane potential, respirationand cellular ROS levels. Trend FOXO3a controls a delicate balance between mitochondrial reactive oxygen species (ROS)-generation and ROS-preventing or detoxifying processes, which is critical for cell death decision in neuronal cells.